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The Main MOE Windows MOE Database Viewer (DBV)

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1 The Main MOE Windows MOE Database Viewer (DBV)
MOE Overview The Main MOE Windows MOE Database Viewer (DBV) Cheminformatics, conformational search, fingerprints, clustering, combinatorial library design The MOE Window (MOE) or ( ) Small molecule bioinformatics, Molecular mechanics, Small molecule visualization, Forcefield applications MOE is a software platform that integrates five main areas of computational life sciences and drug discovery: These areas are normally accessed with the four windows shown above: The MOE Window ( MOE ) is the main window for molecular modeling, 3D structure editing, visualization, force field based simulations and structure-based design. It displays the 3D molecular data currently loaded in the system. The MOE Window is launched when MOE is started. The Sequence Editor ( SE ) is the main launching point for protein sequence and 3D structure analysis applications, including a complete sequence to structure homology modeling suite. It shows the chain and residue data loaded in the system. The Database Viewer ( DBV ) is the main launching point for molecular database applications, including QSAR tools, diverse subset selection and clustering. It is the window in which MOE molecular databases (mdb) are viewed. The SVL Commands Window ( CLI or svl> ) is the primary access point for SVL commands. The Commands Window shows a running log of the SVL commands issued in the current MOE session, and the results of many applications are written here. Other windows have a one line SVL command entry point (CLI), but their results are all written to the SVL Commands Window. SVL Commands Window (CLI) Custom SVL, interactive scripting, session logging Sequence Editor (SE) Protein bioinformatics, homology modeling, sequence analysis Copyright © 2006 Chemical Computing Group, Inc.

2 Intro 1: The MOE Window Used for: Building small molecules
MOE Overview Intro 1: The MOE Window Used for: Building small molecules Molecular mechanics Structure-based drug design Docking SCF Calculations Molecular dynamics Flexible alignment PH4 elucidation Conformational searching Our starting point is the main window, referred to as the MOE Window. The MOE Window is the main access point for most of MOE’s GUI applications. Shown in this slide, the MOE Window consists of: 3D Rendering Area: Three-dimensional molecular and graphic objects may be displayed, edited, rotated and translated. Main Menu Commands: Launches most of MOE’s applications. Right Hand Side Button Bar (RHS): Contains buttons for convenient access to commonly used MOE windows such as the Sequence Editor and frequently used tools such as molecular mechanics minimization and centering the 3D view. These commands will be denoted by RHS | Command throughout the text. Task Cancel Button: Cancels any tasks that are currently running. SVL Command Line (CLI): SVL commands may be entered line by line. Footer Pager Bar: Provides three (3) pages: Dials: For rotation and translation of the system. 3D: For setting depth cue and Z-clip parameters. View: For saving and reloading various views of the system. Copyright © 2006 Chemical Computing Group, Inc.

3 Intro 2: The Sequence Editor
MOE Overview Intro 2: The Sequence Editor Used for: Protein bioinformatics Sequence alignment Homology searching Homology modeling Target family analysis RCSB download Consensus modeling PDB searching Anatomy of the Sequence Editor Sequence Editor (SE) Menu: The main menu bar for the Sequence Editor. Commands issued from here are preceded with SE (e.g., SE | File | Open). Chain Number: The number of the chain in the system; the color of the number is the ‘chain color’, which can be used in rendering. Residues: The residues in each chain (three-letter and single letter modes are supported). Alignment Ruler: Shows the relative position of residues in protein alignments. It can be used to select columns of residues, and identify residues of interest based on their sequence position. SE | Display: Options include: Compound Name Actual Secondary Structure Single or Triple Letter Residue Names Backbone Hydrogen Bonds Residue Indices and UID SE | Measure: Protein Contacts, Ramachandran Plots, Protein Report. Copyright © 2006 Chemical Computing Group, Inc.

4 Intro 3: The MOE Database Viewer
MOE Overview Intro 3: The MOE Database Viewer Used for: Cheminformatics QSAR Conformation search output Dynamics output Flexible alignment output Docking output Clustering Fingerprints Similarity search Diverse subset Data correlation Combinatorial library design R-group preparation PH4 searching Washing / Preprocessing The MOE Database Viewer DBV is the main launch point for MOE’s QSAR and small molecule database applications. These include:  Histogram, 2D and 3D data plotting. Recording, viewing and analyzing conformational search results. QSAR descriptor calculation. Cluster analysis and Principle component analysis. Tools for building QSAR models using Linear Regression, Binary-QuaSAR and Recursive Partitioning. Substructure searching based on SMILES and SMARTS strings. Combinatorial library enumeration and analysis. The MOE database is a molecular spreadsheet that may contain three different data types: Character, Numeric (integer, floating point), and Molecular. 3D structures can be rotated and zoomed directly in a database cell. Molecular data can be easily transferred between the DBV and MOE Windows. The MOE Database Viewer (DBV) is a direct to disk view of a MOE database file. Because of the direct to disk nature of the DBV, changes are updated to disk immediately (no UNDO!). Copyright © 2006 Chemical Computing Group, Inc.

5 Intro 4: The SVL Commands Window
MOE Overview Intro 4: The SVL Commands Window Used for: Custom SVL Interactive scripting Session logging What is SVL (Scientific Vector Language)? Command language of MOE. Script language of MOE. Applications programming language of MOE. Characteristics of SVL: High-level language - vector based-Interactive and compiled (byte code). Very concise code (10 times less than C or Fortran). High-performance. Inherently portable. MOE is a hybrid byte-code / native code system: Base system is written in C (native code - executable only). Applications are written in SVL (byte code - source code). Port of base system automatically ports SVL programs. Collection-oriented (vector) operations deliver efficient and concise programs (small line count). Copyright © 2006 Chemical Computing Group, Inc.

6 Layout of Course Main MOE Window: Introduction to the Sequence Editor
MOE Overview Layout of Course Main MOE Window: Opening/saving files Building molecules Rendering Introduction to the Sequence Editor Introduction to the Database Viewer Basics of molecular mechanics and conformational searching Basics of cheminformatic analysis with the Database Viewer Comments on SVL Copyright © 2006 Chemical Computing Group, Inc.

7 1. Structure of the MOE Window
MOE Overview 1. Structure of the MOE Window Task Cancel Button Main Menu Commands RHS Button Bar SVL Command Line Popup menu 3D Rendering Area Our starting point is the main window, referred to as the MOE Window. The MOE Window is the main access point for most of MOE’s GUI applications. 3D Rendering Area: Three-dimensional molecular and graphic objects may be displayed, edited, rotated and translated. Main Menu Commands: Launches most of MOE’s applications. Right Hand Side Button Bar (RHS): Contains buttons for convenient access to commonly used MOE windows such as the Sequence Editor and frequently used tools such as molecular mechanics minimization and centering the 3D view. These commands will be denoted by RHS | Command throughout the text. Task Cancel Button: Cancels any tasks that are currently running. SVL Command Line (CLI): SVL commands may be entered line by line. Footer Pager Bar: Provides three (3) pages: Dials: For rotation and translation of the system. 3D: For setting depth cue and Z-clip parameters. View: For saving and reloading various views of the system. Footer Pager Bar Copyright © 2006 Chemical Computing Group, Inc.

8 MOE Menu Command Conventions
MOE Overview MOE Menu Command Conventions Commands from the MOE Window are preceded by MOE or () (Render | Backbone | Color | Chain Color) or (MOE | Render | Backbone | Color | Chain Color) Throughout the course, menu commands will be denoted with vertical bars separating commands. For example, the menu command above reads: (MOE | Render | Backbone | Color | Chain Color) Commands from the main MOE Window are preceded by MOE or nothing. Commands issued from the Database Viewer are always preceded by DBV. Commands issued from the Sequence Editor are always preceded by SE. Commands issued from a Command Line Interface (CLI) are always preceded by svl>. Copyright © 2006 Chemical Computing Group, Inc.

9 Mouse Conventions in MOE
MOE Overview Mouse Conventions in MOE General Mouse Actions 3-Button Mouse – 2-Button Mouse Mapping LEFT - Selecting objects, menu commands MIDDLE - Rotating, translating moving objects Press and release <Alt> key RIGHT - SE and DBV Popup menus Notes: The following equivalences between buttons on a three-button and a two-button mouse are shown. In general, the mouse has the following actions in MOE: Left Select objects / issue menu commands Middle Moving Objects (Right button on a 2-button mouse) Right Popup menus (SE and DBV only) (press and release the <Alt> key ) Copyright © 2006 Chemical Computing Group, Inc.

10 Input / Output File Formats in MOE
MOE Overview Input / Output File Formats in MOE MOE can read various input formats, e.g. MOE, PDB, SD etc. A variety of export file formats are possible, e.g. MOE, Tripos MOL2 etc. Picture files may be generated for publications or presentations. MOE can handle a variety of input and output file types, e.g.: Input: MOE, SD, PDB, Tripos Mol2, SMILES One may paste from ISIS Draw, ACD ChemSketch and ChemDraw. Output: MOE, MDLMol, Tripos Mol2, PDB, Macromodel, MSI XTL, SMILES In addition, one may capture or print PNG, GIF, JPEG or postscript files. Copyright © 2006 Chemical Computing Group, Inc.

11 Opening Files in MOE – (File | Open)
MOE Overview Opening Files in MOE – (File | Open) Current Path/ Directory Change Working Directory (CWD) Path Text Field Enforce File Type ‘..’ go up a Directory Operations to Perform on selected file(s) Recent Directories List The MOE File Open panel is initiated with the GUI command File | Open. Current Path/Directory: Lists the path to the current working directory. Change Working Directory (CWD): Changes the working directory to the directory listed. Recent Directories List: Pull-down menu lists MOE installation and recently used directories. Path Text Field: Path and directory may be entered here. Enter drive letters here (e.g., f:/ ) to change drives. Operations: Select desired operation to perform on file; options may include open file in 3D rendering area, import into a database, append to a database, etc. Enforce File Type: Forces the reading of a file as a certain type;. Directory/File List: Select files to be opened. Use the <Ctrl> modifier to select multiple files. <Shift> modifier to select a range. The open operation will apply to ALL the files selected in the list. Directory/ File List Open file in text editor Open file into MOE Copyright © 2006 Chemical Computing Group, Inc.

12 Exercise: Opening a File
MOE Overview Exercise: Opening a File Open the File Open panel (File | Open). Use the pull-down menu to switch to the $MOE/sample/mol directory. Find the file $MOE/sample/mol/sulph_quin.moe Open MOE file into the MOE Window by either: Selecting the file and clicking OK or Open in MOE. Double left-clicking on the filename. Copyright © 2006 Chemical Computing Group, Inc.

13 Exercise: Opening a File (cont.)
MOE Overview Exercise: Opening a File (cont.) Center the View (Render | View or RHS | View). Render the molecule in stick mode (Render | Stick). Note: When a file is opened, the molecule may be out of the center of view. If you open a 3D structure file and nothing appears, always try centering the view to ensure that the molecule is not simply out of view. Up to 8 views may be saved and restored from the View page in the Footer pager This molecule is 8-Sulphonyl-1H-quinoline-2-one. Copyright © 2006 Chemical Computing Group, Inc.

14 Exercise: Manipulate molecule in 3D Window
MOE Overview Exercise: Manipulate molecule in 3D Window Right Click: Popup menu Middle click: Change center of rotation Left Click: Select atoms one at a time Left Click in Empty Space: To de-select to clear Middle Drag: XY Rotate Ctrl Middle Drag or Scroll wheel Zoom in/out Left Drag: Selection Box Copyright © 2006 Chemical Computing Group, Inc.

15 Exercise: Render molecule
MOE Overview Exercise: Render molecule Render as ball and stick, label all atoms by name, and show H-Bonds MOE | Render | Draw | Hydrogen Bonds Mode | Ball and Stick 3. Label | Name MOE | Render can be used to show the hydrogen bonds, in addition to van der Waals contacts, etc in this small molecule. The elements may be labelled also, and the atoms and bonds depicted in different ways. Note the options on the right-hand button bar for the convenience of the user (e.g. molecule depiction, element labelling etc.) 4. Label | Clear Copyright © 2006 Chemical Computing Group, Inc.

16 Exercise: Saving a picture (1)
MOE Overview Exercise: Saving a picture (1) 1. Choose MOE | File | Save 2. Click on MkDir to create a new directory called ‘course’ 3. Click on Set CWD to set as the new working directory It is always good practice to define the current working directory (CWD) for a particular project to store files. The CWD will be used as the default when opening or saving files, saving the user the trouble of ‘browsing’ to the appropriate directory. Copyright © 2006 Chemical Computing Group, Inc.

17 Exercise: Saving a picture (2)
MOE Overview Exercise: Saving a picture (2) Choose Save ‘Picture’ Enter the filename ‘sulph_quin.png’ Choose Format ‘PNG’ Finally click on Save A variety of formats may be specified for saving picture files, e.g. JPEG, PNG, GIF, BMP. Copyright © 2006 Chemical Computing Group, Inc.

18 Rendering 2D Depicted Molecules
MOE Overview Rendering 2D Depicted Molecules 1. MOE | Edit | Automatic | Depict as 2D Press ‘Export Bitmap’ to save picture as ‘sulph_quin2.png’ Press OK Press Close Saving 2D depictions is useful for communicating ideas for structures to chemists, for presentations or for publications. Copyright © 2006 Chemical Computing Group, Inc.

19 Drawing Molecular Surfaces
MOE Overview Drawing Molecular Surfaces Create Molecular Surfaces via the Molecular Surface panel (MOE | Compute | Surfaces and Maps) Manage surfaces and other graphics objects with the Graphic Object Manager (MOE | Window | Graphic Objects) Copyright © 2006 Chemical Computing Group, Inc.

20 Molecular Surfaces and Maps
MOE Overview Molecular Surfaces and Maps Tool for active site analysis Integration of three applications: Molecular Surfaces, Contact Preference Maps and new Electrostatic Maps Easy control of definition for atom sets Automatic handling of surface names for easy comparisons Build molecular surfaces Gaussian, Connolly and VDW Color by various properties Predict contact preferences Plot knowledge based potentials for hydrophilic and hydrophobic contacts Calculate electrostatic maps Plot electrostatically preferred positive, negative and neutral regions Copyright © 2006 Chemical Computing Group, Inc.

21 Exercise: Drawing Molecular Surfaces (1)
MOE Overview Exercise: Drawing Molecular Surfaces (1) Draw a surface around the inhibitor by first choosing (MOE | Compute | Surfaces and Maps) using the default options Press Apply Copyright © 2006 Chemical Computing Group, Inc.

22 Exercise: Outputting the system… to the printer
MOE Overview Exercise: Outputting the system… to the printer To print the current MOE 3D window choose MOE | File | Print... Printer or Postscript file Landscape/Portrait Header Footer Copyright © 2006 Chemical Computing Group, Inc.

23 Exercise: Outputting the system… to various formats
MOE Overview Exercise: Outputting the system… to various formats Save the current MOE 3D window. MOE | File | Save... 2. Enter filename to save ‘my_sulph_quin.moe’ Choose Save: Molecule and Format: .moe. To save surface, select Graphics:All Click on Save Copyright © 2006 Chemical Computing Group, Inc.

24 Exercise: Close System and Open Builder
MOE Overview Exercise: Close System and Open Builder Close the current system (MOE | RHS | Close) 2. Open the Builder (MOE | RHS | Builder) 3D structure editing tools are mostly accessed from the Edit menu: Edit | Add Hydrogens/ Polar Hydrogens/ Hydrogens and Lps: H’s and LP’s are added to the selected atoms, or to all atoms if no atoms are selected. Edit | Automatic: Atom typing and connecting tools for fixing structures with bad bonding patterns. Edit | Builders: Fragment based builders. Edit | Delete: Delete selected subset; If no atoms are selected, an interactive delete prompt will appear, allowing deletion of atoms one at a time (press ‘Esc’ to exit the prompt). Edit | Fix/Unfix: Fixed atoms do not move; fixing atoms is useful in structure editing and in simulations. Edit | Meters: A prompt for measuring distances, angles or torsions. Edit | Restraints: A prompt for setting MM restraints. Edit | Interactive Superpose: A tool for optimally superposing molecules based on selected point sets. Edit | Polymerize: Polymer builder. Edit | Periodic Box: Create periodic box and boundary conditions. Copyright © 2006 Chemical Computing Group, Inc.

25 MOE Overview The Molecule Builder Other atom types, including dummy atom at centroid Edit or Add Element Edit Ionization State Edit Chirality Fragment substitution buttons Enter Fragment SMILES string Edit: Compound Name Bond Length Bond Angle Torsion MOE Builders are fragment based builders. Pressing a fragment button either substitutes the fragment onto the selected atom(s) or creates the fragment free in space if no atoms are selected. Library of functional groups Undo button Copyright © 2006 Chemical Computing Group, Inc.

26 Exercise: Build a molecule
MOE Overview Exercise: Build a molecule Press Select C Press Select C Press Copyright © 2006 Chemical Computing Group, Inc.

27 Exercise: Build a molecule (cont.)
MOE Overview Exercise: Build a molecule (cont.) Press Shift-select 2 C <Shift> Shift-select 2 C Press <Shift> Copyright © 2006 Chemical Computing Group, Inc.

28 Exercise: Build a molecule (cont.)
MOE Overview Exercise: Build a molecule (cont.) Select H Press Select H Press times Prior to adding the extra four carbon atoms, we have 8-Sulphonyl-1H-quinoline-2-one, which was the molecule that we opened earlier. Copyright © 2006 Chemical Computing Group, Inc.

29 Exercise: Build a molecule (cont.)
MOE Overview Exercise: Build a molecule (cont.) Press Press Select H Press Deselect H Copyright © 2006 Chemical Computing Group, Inc.

30 Exercise: Energy Minimize
MOE Overview Exercise: Energy Minimize RHS | Minimize We will examine energy minimisation in more detail later when we look at Molecular Mechanics. Copyright © 2006 Chemical Computing Group, Inc.

31 Save Molecule Save the current MOE 3D window as a MOE file.
MOE Overview Save Molecule Save the current MOE 3D window as a MOE file. MOE | File | Save... Enter filename to save ‘my_first_molecule.moe’ Save ‘Molecule’ Choose Format ‘MOE’ 2. Press Save Copyright © 2006 Chemical Computing Group, Inc.

32 Protein and Carbohydrate Builders
MOE Overview Protein and Carbohydrate Builders MOE | Edit | Build | Protein or SE | Edit | Protein Builder The Protein Builder allows specification of the backbone geometry by either standard secondary structure type (e.g., helix, extended) or by custom psi/phi angle specification. Unlike the Molecule Builder and the Carbohydrate Builder, the Protein Builder does NOT add fragments to selected atoms; peptide chains are constructed without being automatically connected to selected atoms. The Protein Builder is opened by the MOE | Edit | Protein Builder command. The Carbohydrate Builder uses a customizable library of monosacharride units as fragments that are connected to a currently selected atom through the link position specified by the link position radio button. The glycosidic torsions can be specified in the torsion angle text fields. Construction of long-chain polysacharrides is facilitated by toggling on the Auto-Select Anomeric O option. The Carbohydrate Builder is opened by the MOE | Edit | Carbohydrate Builder command. MOE | Edit | Build | Carbohydrate Copyright © 2006 Chemical Computing Group, Inc.

33 Selecting Atoms with the Left Mouse Button
MOE Overview Selecting Atoms with the Left Mouse Button <Ctrl>-Left Click: Auto-extend selection to residue Left Click: Select atoms one at a time <Ctrl> <Shift> <Shift>-Left Click: Add to / toggle atom selection Action Left mouse button Select an atom Click on the atom Toggle selection state of an atom <Shift>-click on the atom Select multiple atoms <Shift>-click on the atom(s) to be selected Auto-extend atom selection to entire residue <Ctrl>-click on an atom in the residue Toggle selection state of all atoms in a residue <Shift>-<Ctrl>-click on an atom in the residue Draw a selection box Click and Drag Rotate around selected bond <Alt>–Drag Note on <Ctrl>-Left Click: There is only one residue in the built molecule, so the whole molecule will be selected. This will be revisited later. Left Drag: Selection Box Copyright © 2006 Chemical Computing Group, Inc.

34 Exercise: Selecting Atoms with the Left Mouse Button
MOE Overview Exercise: Selecting Atoms with the Left Mouse Button Use Left-Click to select atoms one at a time. Use Left-Drag to draw a selection box. Use <Shift>-Left Click extend/toggle atom selections. Use <Ctrl>-Left Click to select entire residues. Left-mouse click in empty space to de-select any atoms. Notes on Selecting Atoms with the left mouse button: Selected atoms appear in an alternate color (usually pink) when rendered as ball or space filling styles. Bond colors remain in the standard for the element type of the elected atoms. In line style, or when atoms are hidden, atoms are denoted by a small, usually pink, square. The <Shift> modifier key toggles selection states. The <Ctrl> modifier key automatically extends the selection to the entire residue. The combination of <Shift> and <Ctrl> modifier keys toggles the selection of entire residues. The modifier keys can be used in conjunction with the drag left selection box. Copyright © 2006 Chemical Computing Group, Inc.

35 Exercise: Fixing/Unfixing Atoms (Edit | Potential | Fix / Unfix)
MOE Overview Exercise: Fixing/Unfixing Atoms (Edit | Potential | Fix / Unfix) Fixing atoms: Left mouse drag to select the atoms to be fixed. Fix the atoms with the command (Edit | Potential | Fix) . Fixed Atoms do not move until unfixed. Unfixing atoms: Select the atoms to be unfixed. Use (Selection | Potential | Fix) to select all the fixed atoms. Unfix the atoms with the command (Edit | Potential | Unfix). Once unfixed the atoms may move. Copyright © 2006 Chemical Computing Group, Inc.

36 Exercise: Fixed atoms and rotatable bonds
MOE Overview Exercise: Fixed atoms and rotatable bonds If two atoms in a rotatable bond are selected <Alt>-Left Drag will rotate about the bond. If no atoms are fixed, the small group rotates by default. <Alt> Drag The larger group can be forced to rotate by fixing an atom in the smaller group FIX this atom <Alt> Drag Copyright © 2006 Chemical Computing Group, Inc.

37 Meters and Measurement
MOE Overview Meters and Measurement (Edit | Measure) or (RHS | Measure…) Choose Distances to measure and display the distance between two atoms. Choose Angles to measure and display the angle between three atoms. Choose Dihedrals to measure and display the dihedral angle between four atoms. Notes: To create meters, choose Edit | Measure in the MOE Window. MOE will prompt you to select the type of measurement and the required number of atoms to use. When selecting the atoms, it you wish to deselect an atom, simply click on it a second time and it will be removed from the selection. The prompt will reflect this change. Once created, the meter appears in the MOE Window as a colored line with a measured value. Meters are automatically updated when atom positions are altered. The actual display of meters in the MOE Window is controlled by the Meters toggle button in MOE | Render | Draw. If meters are not appearing, the Meters toggle might have been turned off. Copyright © 2006 Chemical Computing Group, Inc.

38 Meters – Creating and Removing
MOE Overview Meters – Creating and Removing To create a meter, choose MOE | Edit | Measure | Distances. To remove it, select the atoms involved, and use RHS | Remove | Distances. The Meters and Restraints panel displays the list of current meters and restraints in the system. This panel allows you to see the values of the meters and restraints, to select or delete any meter or restraint, and to modify the weight or target value of a restraint. Note, however, that you cannot create meters or restraints from this panel. To open the Meters and Restraints panel, choose MOE | Window | Meters and Restraints. The panel shows meters and restraints separately, depending on which of the buttons at the top of the panel has been pressed: Press Meters to display the list of currently measured meters. Press Restraints to display the list of current restraints in place. The Weight and Target values apply to restraints only. The Target is the value at which you want to restrain the geometric property (bond distances in angstroms, bond angles and dihedrals in radians). The weight factor determines the strength of the restraint relative to the total energy of the molecule. Once the target and weight values have been edited, you have to press the Apply button or Return for the changes to take effect. Copyright © 2006 Chemical Computing Group, Inc.

39 MOE Overview CLI Prompt Menus One-line CLI Prompt menus occupy the SVL Command Line at the top of the window Press (Esc) to exit the prompts or choose to delete the process using the ‘Cancel’ button on the top right. Notes: CLI Prompt menus appear in the MOE Window, the Sequence Editor and in the Database Viewer. Many interactive commands such as Edit | Meters invoke CLI Prompts; these one-line menus occupy the SVL Command Line at the top of the window (see above). The mouse pointer will often change to cross-hairs in this state. Pressing the escape (Esc) key exits this kind of prompt and returns the CLI and the mouse pointer to their normal states. A process may also be terminated using the ‘Cancel’ button on the top right. Copyright © 2006 Chemical Computing Group, Inc.

40 MOE Selection Menu Extend selection set Deselect all atoms
MOE Overview MOE Selection Menu Extend selection set Deselect all atoms Invert current selection Knowledge-based selectors for different parts of protein/ligand bound structures Notes: Selection | Clear: Deselect all atoms. Selection | Invert: Invert atom selection states. Selection | Extend: Extends current selection set to a range of options (shown). Selection | Ligand, Pocket, Receptor, Solvent: Knowledge-based tools for selection of different parts of protein/ligand structure, modeled or from crystallographic measurements. Selection | Attachment: Selects designated attachment points. Selection | Elements: Select by element. Selection | Geometry: Select by geometry (sp, sp2, sp3, etc.). Selection | Potential: Select by various atom properties (chirality, fixed,etc.). Selection | Protein: Select alpha and beta carbons, backbone and sidechain atoms. Selection | Atom Selector: Advanced Atom selection tool for: Extending selections with proximity. Selection by substructure. Logic operations on selection sets. Selection | Save: Save current selection set (one level). Selection | Restore: Restore saved selection. Selection | Synchronize: Selection state of residues is coordinated with the Sequence Editor. Atom Selection Tool for advanced selecting Pull down menus for selection by property, element, extension or other criteria Save and Restore selection sets Selection state of residues is coordinated with the Sequence Editor Copyright © 2006 Chemical Computing Group, Inc.

41 The Atom Selector MOE | Selection | Atom Selector
MOE Overview The Atom Selector MOE | Selection | Atom Selector General Selection actions Selection Restrictions Logic Operations Save and Load selection sets; create named sets Select by name Select by elements and atom types Select by SMILES string substructure Other Selection Options: Accessibility Chirality Connectivity Geometry General Pharmacophore Protein (e.g. alpha carbon) Notes: Open the Atom Selector with: Selection | Atom Selector or RHS | Atom Selector. Restrict To: Restrict selection to a subset of atoms. Save/Load Set: Save and re-load up to 10 selection sets. Create named sets. Extend: Extend current selection to (e.g.,): Bonded to. Molecule. Proximity-select all atoms within a Radius of current selection. Operations: Logic operations that apply when forming selection: Or: Adds to current selection based on selector action. And: Restrict selection action to current selection set. Deselect: Deselect atoms based on selector action. Replace: Replace current selection with selection based on selector action. Extend Selection Criteria Copyright © 2006 Chemical Computing Group, Inc.

42 Moving Atoms with the Middle Mouse Button
MOE Overview Moving Atoms with the Middle Mouse Button <Alt> Middle Drag: XY Rotate center of rotation Middle Drag: <Alt> <Shift>-Middle Drag: XY Rotate selected only Middle click to center on atom XY Translate selected only XY Translate <Shift>Middle Drag: Zoom in/out <Ctrl>Middle Drag: Action Middle mouse button Translate view along xy axes <Shift>-Middle drag Rotate view around xy axes Middle Drag in rendering area Rotate view about z axis only Drag in perimeter of rendering area Zoom in/out <Ctrl>-Middle drag Rotate Selected atoms only <Alt>-Middle drag Translate Selected atom only <Alt>-<Shift>-Middle drag Set Atom as Center of Rotation Middle Click on atom Copyright © 2006 Chemical Computing Group, Inc.

43 Exercise: Moving Atoms with the Middle Mouse Button
MOE Overview Exercise: Moving Atoms with the Middle Mouse Button View the coordinate system (Render | Draw | Coordinate Axes). Rotate view about the XY axes (Middle Drag). Translate view (<Shift>-Middle Drag). Middle click on the carbonyl O to move the center of rotation. Remove the coordinate axes by de-selecting (Render | Draw | Coordinate Axes) Deselect all atoms (Left-click in space or (Selection | Clear)). Move a selected subset with <Alt>-Middle Drag (rotate) <Shift><Alt>Middle Drag (translate). Notes: The <Alt> key modifier enables you to move selected atoms with respect to unselected atoms. If two atoms in a rotatable bond A-B are selected, <Alt>-Left Drag will rotate the structure about that bond. By default, the smaller of the groups (A or B) will move in the rotation; the larger group can be made to rotate by fixing an atom in the smaller group. Center of rotation: Middle clicking on an atom will shift the center of rotation to it. Middle clicking in empty space to restore the center of rotation to the center of mass. Visualize the center of rotation and axes: MOE | Render | Draw | Coordinate Axes. Copyright © 2006 Chemical Computing Group, Inc.

44 MOE Render Menu Center, Save and Load views
MOE Overview MOE Render Menu Center, Save and Load views Draw H-bonds, VDW contacts, label options, coordinate axes, etc. Stereo viewing options: Quad-Buffer, Over-Under, Interlace, Left-Right, Parallel Protein/DNA backbone rendering Atomic/Molecule object rendering Hide and Show various sets Basic coloring Atom Labeling menu Detailed atom and label style menu Setup of default colors and object dimensions. Copyright © 2006 Chemical Computing Group, Inc.

45 Exercise: Small Molecule Rendering
MOE Overview Exercise: Small Molecule Rendering Rendering actions apply to: All atoms (if none are selected) Selected atoms only (if there are selected atoms) Deselect all atoms. Use Left drag click to select part of the molecule. Render it as space filling (Render | Space Filling). Select other parts of the molecule using left-drag or other methods, and render them as stick, ball and stick, or line. Select and render as ‘Space Filling’ Notes: Rendering actions apply to: All atoms if no atoms are selected. Selected atoms only if there are any selected atoms. Select group and render as ‘Stick’ Copyright © 2006 Chemical Computing Group, Inc.

46 Protein Backbone Rendering
MOE Overview Protein Backbone Rendering MOE | Render | Backbone or MOE | Popup | Backbone Turn off backbone Various Backbone rendering styles Backbone coloring options Notes: If you color the backbone by Residue Color, the backbone will be colored according to the color of the residue names in the Sequence Editor, the default of which is black. Copyright © 2006 Chemical Computing Group, Inc.

47 Exercise: Open PDB file prior to rendering complex
MOE Overview Exercise: Open PDB file prior to rendering complex Close the current system: MOE | File | Close Select the file MOE | File | Open $MOE/sample/mol/1pph.pdb. Press ‘Load PDB File’. A variety of options are available in the PDB File panel. Choose to centre the view and press ‘OK’. The PDB reader has a number of load and read options: Auto-connect Atoms. If on, atoms will be automatically bonded after CONECT records are applied. This option is useful if CONECT records are missing from a PDB file. If off, no additional bonding is done. Note that atoms of amino acid residues are always automatically bonded. Import All Models. If on, all models in the PDB file will be imported. Each imported model will be assigned a unique chain tag. If off, only the first model in the file will be imported. Integrate SEQRES Data. If on, then after reconciling ATOM and SEQRES records, empty residues implied in SEQRES records are created. Also, modified residues will be named by standard residue names as specified in MODRES and SEQADV records. Ignore Waters. If on, then all waters in the PDB file will be ignored. Ignore Hetero. If on, then all hetero residues in the PDB file will be ignored. Auto-tag. If on, then any chain with an empty tag will receive the name of the PDB file as its tag. This ensures that chains which originate from a single file are grouped together by their tags even in the case where no tag is specified in the file. Create Separate Entries for Each Model. If on, each individual model from a multiple model PDB file is written to a separate database entry. Otherwise, all models are written into a single entry. This option is available only if Import All Models is on. Copyright © 2006 Chemical Computing Group, Inc.

48 Exercise: Rendering Trypsin with Ligand
MOE Overview Exercise: Rendering Trypsin with Ligand Select the water molecules (Selection | Solvent) and delete them (RHS | Delete). Select the ligand(s) (Selection | Ligand) and render as space filling (Render | Space Filling). Use Render | Color to select a desired colour for the selected atoms (green). Deselect the atoms Draw a backbone ribbon through the selected atoms (Render | Backbone | Slab Ribbon). Color the backbone by Chain Color (Render | Backbone | Color | Chain Color). Hide the selected protein atoms (Render | Hide | Receptor). Click on empty space to clear selection state. Copyright © 2006 Chemical Computing Group, Inc.

49 Exercise: Protein-Ligand Pocket Rendering
MOE Overview Exercise: Protein-Ligand Pocket Rendering Turn the backbone off (MOE|Popup|Backbone|None) Show ligand and pocket (MOE|Popup|Show|Ligand, Pocket) Label the residues (MOE | RHS | Label | Residue) Draw H-bonds (Render | Draw | Hydrogen Bonds) Center the image (RHS | View) which should now look like the image on the left. Save the system as a MOE file, MOE | File | Save trypsin_pocket.moe Copyright © 2006 Chemical Computing Group, Inc.

50 Contact Statistics r P Preference for Hydrophilic Contacts
MOE Overview Contact Statistics Calculate and display probability of finding hydrophobic or hydrophilic contact at a point P relative to an atom. The contacts are derived from PDB x-ray structure statistics. Preference for Hydrophilic Contacts Preference for Hydrophobic Contacts v u r P Copyright © 2006 Chemical Computing Group, Inc.

51 Contact Statistics (cont.)
MOE Overview Contact Statistics (cont.) Contact Statistics can be used to highlight directional packing preferences on interaction surfaces: Hydrophilic contacts for polar H Hydrophobic contacts above and below pi system Interaction Surface Contacts statistics on top of interaction surface Copyright © 2006 Chemical Computing Group, Inc.

52 Exercise: Contact Statistics in Pocket
MOE Overview Exercise: Contact Statistics in Pocket Open the Contact Statistics panel: MOE | Compute | Surfaces and Maps Setup the panel as follows Surface: Contact Preference Press Apply. Contact Statistics The purpose of the Contact Statistics application is to calculate, from the 3D atomic coordinates of a receptor, preferred locations for hydrophobic and hydrophilic ligand atoms. Although forcefield contours can provide a good indication of regions of strong van der Waals attraction, it is more difficult to use electrostatics terms to classify regions as being hydrophilic or hydrophobic. Purely distance-based methods such as distance pseudo-potentials and forcefields currently cannot capture the angular preferences for particular atom types. Although the contact statistics are derived statistically from PDB data, they often coincide closely with the interaction surface. Contact Statistics can be used to highlight directional packing preferences when overlaid upon interaction surfaces, highlighting highly favorable binding locations on the receptor surface. 5. Save to a MOE file (File | Save) ‘trypsin_csats.moe’ toggling on Graphics: All in panel Copyright © 2006 Chemical Computing Group, Inc.

53 Exercise: Receptor Molecular Surfaces
MOE Overview Exercise: Receptor Molecular Surfaces Close the current system. (File | Close). Disable hydrogen bond selection by de-selecting MOE | Render | Draw | H bonds Open the files (MOE | File | Open ) $MOE/sample/mol/biotin.moe. $MOE/sample/mol/biotin_rec.moe. Calculate partial charge (MOE | Compute | Partial Charge) and enable “Adjust Hydrogens and Lone Pairs as Required” Draw a electrostatic surface about the pocket (MOE|Compute|Surfaces and Maps) Name the surface ‘Pocket Surface’ Color by Electrostatics Press Apply Notes: Both biotin.moe and the biotin_rec.moe files were made from a PDB file. This is the biotin-streptavidin system. The rendering and the view of the system are saved in the MOE file. Copyright © 2006 Chemical Computing Group, Inc.

54 Exercise: Receptor Molecular Surfaces
MOE Overview Exercise: Receptor Molecular Surfaces To isolate the pocket atoms, press Isolate on the panel Turn off backbone (MOE|Popup|Backbone|None) Select the pocket atoms (MOE|Popup|Select|Pocket) Label the residues with the residue name (MOE|RHS|Label|Residue) Copyright © 2006 Chemical Computing Group, Inc.

55 Exercise: Ligand Molecular Surfaces
MOE Overview Exercise: Ligand Molecular Surfaces Now draw a molecular surface of the ligand (MOE | Compute | Surfaces and Maps) selecting the defaults, but changing the Name to: Ligand Surface, and selecting Atoms: Ligand Atoms Press Apply Copyright © 2006 Chemical Computing Group, Inc.

56 Exercise: Biotin receptor surface (cont.)
MOE Overview Exercise: Biotin receptor surface (cont.) To view the different surfaces, go to (MOE | Window | Graphic Object) Select Pocket Surface Press Hide Select both surfaces (Shift Left mouse click) Press Toggle to switch between surfaces Notes: Toggle the ligand surface on and off – see how it fits with the receptor surface. Note that the molecular surface penetrates through the pocket surface at places where there is a hydrogen bond or other close interactions. Copyright © 2006 Chemical Computing Group, Inc.

57 Surfaces: Backface Culling and Visualization
MOE Overview Surfaces: Backface Culling and Visualization Note the transparency options for the front (TF), and the back (TB) Set the slide on TB, and rotate the system to view the backface culling Copyright © 2006 Chemical Computing Group, Inc.

58 Ligand Interactions Automatic 2D protein-ligand interaction diagrams
MOE Overview Ligand Interactions Automatic 2D protein-ligand interaction diagrams Application of MOE's automatic 2D depiction algorithm Easily identify polar, hydrophobic, acidic and basic residues Visualize solvent exposed ligand atoms and residues Visualize sidechain and backbone acceptor and donor interactions Visualize 3D Contacts Display hydrogen bonds between ligand, receptor/solvent and metal ligation Score estimates strength of hydrogen bond Report protein-ligand interaction data Textual listing of interactions with scores Export 2D schematic to a picture Choose between png, gif, jpeg, bmp and copy to clipboard Copyright © 2006 Chemical Computing Group, Inc.

59 Exercise: 2D Protein-Ligand Interactions
MOE Overview Exercise: 2D Protein-Ligand Interactions Hide all surfaces (MOE | Window | Graphic Object). Select and Hide each surface Open MOE | Compute | Ligand Interactions Copyright © 2006 Chemical Computing Group, Inc.

60 Exercise: Protein-Ligand Interactions
MOE Overview Exercise: Protein-Ligand Interactions acidic residue amount of ligand contact polar residue substitution contour sidechain donor solvent exposure greasy residue backbone donor/acceptor Copyright © 2006 Chemical Computing Group, Inc.

61 Exercise: Protein-Ligand Interactions
MOE Overview Exercise: Protein-Ligand Interactions In the Ligand Interactions panel, select 3D Contact Style Turn ON Residue H-bond Distance. Residue hydrogen bonds are scored and distance metrics are drawn in the main MOE window In the main MOE window, observe the relative strength of the ideal hydrogen geometry, shown as dotted lines Copyright © 2006 Chemical Computing Group, Inc.

62 2. The Sequence Editor Open SE… (MOE | SEQ) or <Ctrl>-Q
MOE Overview 2. The Sequence Editor The SE Displays a ‘2D’ view of the molecular data Open SE… (MOE | SEQ) or <Ctrl>-Q MOE Window - 3D molecular data is displayed in the Sequence Editor as 2D data: bound ligand(s) protein chain(s) water chain(s) The Sequence Editor: The main launch point for protein applications, including structure modification such as mutation, and protein modeling applications such as multiple sequence alignment, structure superposition, homology modeling and visualization. A 2D display of the molecular system currently loaded in MOE. The system is organized into a hierarchy meant to reflect biopolymers and their associated small molecules and counter-ions. Allows you to organize and modify molecules by chains and residues. Chain and residue objects in the Sequence Editor can be used to manipulate their corresponding 3D objects in the main MOE Window. Objects in SE can be used to manipulate objects in MOE Window (ensure Selection | Synchronize is enabled) Secondary Structure in SE is displayed as colored bars Copyright © 2006 Chemical Computing Group, Inc.

63 Anatomy of the Sequence Editor (SE)
MOE Overview Anatomy of the Sequence Editor (SE) SE Menu Alignment Ruler Chain Label Residues Chain Number Notes: Anatomy of the Sequence Editor Sequence Editor (SE) Menu: The main menu bar for the Sequence Editor. Commands issued from here are preceded with SE (e.g., SE | File | Open). Chain Number: The number of the chain in the system; the color of the number is the ‘chain color’, which can be used in rendering. Residues: The residues in each chain (three-letter and single letter modes are supported). Alignment Ruler: Shows the relative position of residues in protein alignments. It can be used to select columns of residues, and identify residues of interest based on their sequence position. SE | Display: Options include: Compound Name Actual Secondary Structure Single or Triple Letter Residue Names Backbone Hydrogen Bonds Residue Indices and UID SE | Measure: Protein Contacts, Ramachandran Plots, Protein Report. Footer Secondary Structure Bars Red = helices Yellow = sheets Blue/Green = H-bonded Turns Copyright © 2006 Chemical Computing Group, Inc.

64 SE Menu Command Conventions
MOE Overview SE Menu Command Conventions Commands from the Sequence Editor are preceded by SE. (SE | Selection | Residue Selector) Notes: Sequence Editor menu commands are always preceded with SE. Commands from the main MOE Window are preceded by either MOE or nothing. Commands issued from the Database Viewer are always preceded by DBV. Commands issued from the Sequence Editor are always preceded by SE. Commands issued from a Command Line Interface (CLI) are always preceded by svl>. Synchronize selection of objects in MOE Window or DBV (via MOE or SE | Selection | Synchronize) Copyright © 2006 Chemical Computing Group, Inc.

65 Data Hierarchy in MOE Notes:
MOE Overview Data Hierarchy in MOE Notes: The hierarchy of molecular data in MOE is summarized below: The system is divided into chain objects, with each subdivided into residue objects. The residue objects themselves are composed of atom objects. The hierarchy can be user specified, and does not necessarily correspond to ‘one chain = one molecule’. The restrictions on the hierarchy are: Atoms must be child objects of residues. Residues must be child objects of chains. A residue may be the child of only one chain, and an atom may be the child of only one residue. Copyright © 2006 Chemical Computing Group, Inc.

66 Exercise: Molecular Hierarchy
MOE Overview Exercise: Molecular Hierarchy For the loaded biotin-streptavidin system, toggle off the molecular surfaces, at MOE | Windows | Graphic Objects. Select the surface and press Hide. Show receptor, using MOE | Render | Show | Receptor. Clear Labels (MOE | RHS | Label | Clear) Open the Sequence Editor (MOE | SEQ). The system should appear as shown: 4. Click in empty space to clear selection state Copyright © 2006 Chemical Computing Group, Inc.

67 Exercise: Molecular Hierarchy (cont.)
MOE Overview Exercise: Molecular Hierarchy (cont.) Color the atoms by chain color (MOE | Render | Color | Chain) Turn on the compound names (SE | Display | Compound Name) Turn on the secondary structure color bars (SE | Display | Actual Secondary Structure). Copyright © 2006 Chemical Computing Group, Inc.

68 Selecting Objects in the Sequence Editor
MOE Overview Selecting Objects in the Sequence Editor Select range of residues Select residues one at a time Select Multiple Residues <Shift> <Ctrl> Notes: Residue Selection Actions Left click on a residue Select a single residue <Ctrl>–Left click on residue Toggle residue selection state Left click on Alignment Ruler Select a column of residues <Shift>–Left click Select contiguous residues <Ctrl>–Left click on Alignment Ruler Toggle column selection state Left-Drag Draw selection box <Ctrl>–Left drag Add to selection with box Left-Click in empty area Clear residue selection Chain Selection Actions Left click on a Chain Number Select a single chain Left click on Chain Label Select all chains <Shift>–Left click on last chain Select contiguous chains <Ctrl>–Left click Toggle chain selection Left click below Chain Numbers Clear chain selection Left Drag: Selection Box Chain Selection: Click: Chains one at a time <Ctrl> Multiple Chains <Shift> a range of chains Copyright © 2006 Chemical Computing Group, Inc.

69 Sequence Editor Popup Menus
MOE Overview Sequence Editor Popup Menus Open the SE Popup menus by right-clicking over the areas shown below: Notes: The Popup menus are brought up by right-clicking over the area pointed to by the arrows in the picture. Chain Popup Menu Right click over a Chain Number Selected Chains Popup Menu Right click over the Chain Label Residue Popup Menu Right click over a residue Selected Residues Popup Menu Right click in empty display Residue Column Right click over the alignment ruler All five Popup menus in the Sequence Editor allow you to select, view, hide or show atoms of a chain, a residue, a group of selected residues, or a residue column (based on alignment). Furthermore, the Residues | Select All option in the Chain and Selected Chains popups selects all residues in a chain or in all selected chains. Copyright © 2006 Chemical Computing Group, Inc.

70 Exercise: Using SE for Protein Rendering
MOE Overview Exercise: Using SE for Protein Rendering Select protein chain (chain 2). Position mouse over chain and use Right mouse button to get Chain popup. Select Backbone | Slab Ribbon, and Backbone |Color | Chain color Hide receptor (Atoms | Hide) Select Chain 1 (ligand) and use popup menu to Render | Space Filling Note that the crystallographic water molecules are still there, but hidden – NOT deleted. Copyright © 2006 Chemical Computing Group, Inc.

71 Exercise: Using SE for Protein Rendering (cont.)
MOE Overview Exercise: Using SE for Protein Rendering (cont.) Close the current system (MOE | RHS | Close) Close all windows except the main MOE window Copyright © 2006 Chemical Computing Group, Inc.

72 3. The MOE Database Viewer
MOE Overview 3. The MOE Database Viewer Molecular Data easily transferred between database and MOE Window Character, numeric and molecular data fields The MOE Database Viewer DBV is the main launch point for MOE’s QSAR and small molecule database applications. These include:  Histogram, 2D and 3D data plotting. Recording, viewing and analyzing conformational search results. QSAR descriptor calculation. Cluster analysis and Principle component analysis. Tools for building QSAR models using Linear Regression, Binary-QuaSAR and Recursive Partitioning. Substructure searching based on SMILES and SMARTS strings. Combinatorial library enumeration and analysis. The MOE database is a molecular spreadsheet that may contain three different data types: Character, Numeric (integer, floating point), and Molecular. 3D structures can be rotated and zoomed directly in a database cell. Molecular data can be easily transferred between the DBV and MOE Windows. The MOE Database Viewer (DBV) is a direct to disk view of a MOE database file. Because of the direct to disk nature of the DBV, changes are updated to disk immediately (no UNDO!). Full 3D molecular structure Copyright © 2006 Chemical Computing Group, Inc.

73 Anatomy of the Database Viewer (DBV)
MOE Overview Anatomy of the Database Viewer (DBV) Menu Bar Field Headers DBV CLI Entry Numbers Data Cells Notes: The Database Viewer (DBV) Window (shown above) contains the following: Menu Bar: The Database menu bar is where most database-oriented applications are launched. Throughout the course, commands initiated from this menu start with DBV. DBV CLI: SVL commands can be entered individually at the Database SVL Command Line Interface. The output and history of commands entered from the database CLI appear in the SVL Commands Window. Entry Numbers: This left-most column is the running index for the entries. Field Headers: This column header describes the data contained in that field. Data Cells: The data cells contain the data, which may be numeric, character, or structural. Copyright © 2006 Chemical Computing Group, Inc.

74 DBV Menu Command Conventions
MOE Overview DBV Menu Command Conventions Commands from the Database Viewer preceded by DBV (DBV | Entry | Show All Entries) Notes: Commands from the main MOE Window are preceded by either MOE or nothing. Commands issued from the Database Viewer are always preceded by DBV. Commands issued from the Sequence Editor are always preceded by SE. Commands issued from a Command Line Interface (CLI) are always preceded by svl>. Copyright © 2006 Chemical Computing Group, Inc.

75 DBV Left Mouse Button Commands
MOE Overview DBV Left Mouse Button Commands Select entries/fields one at a time <Ctrl> Select multiple entries/fields <Shift> Select range of entries/fields Notes: Mouse Actions in the DBV Left drag on cell Expand/Contract cell Left double-click on molecule Copy molecule to/from MOE Left double–click on data Edit data Left click on entry # Select entry Modifier keys used in conjunction with the left mouse button allow multiple field and entry selections. <Shift>-Left clicking on a range of entries or fields will select a range. <Ctrl>-Left clicking on an entry number or field name toggle its selection. Middle drag on a molecule will rotate a molecule in the cell. <Ctrl>-Middle drag on a molecule will zoom on molecule in cell. Right mouse click (or pressing and releasing the <alt> key) will invoke the Popup menus. Copyright © 2006 Chemical Computing Group, Inc.

76 MOE Overview DBV Popup Menus The Popup Menus are invoked with the right mouse button Notes: The Popup menus are invoked by either right-clicking the mouse or pressing and releasing the <Alt> key when the mouse cursor is positioned above the area pointed to in the picture. Using Popup menus, the data may be: Edited. Added or deleted. Sorted. Hidden. Transferred to and from the MOE Window (molecular data). Selected or deselected. Copyright © 2006 Chemical Computing Group, Inc.

77 Exercise: Opening a MOE Database Viewer
MOE Overview Exercise: Opening a MOE Database Viewer (File | Open) Select the file $MOE/sample/mol/opiates_analog.mdb. Open in a database viewer (Open in Database Viewer). Notes: A new MOE database may be created with the commands: (MOE | File | New | Database) or (DBV | File | New). An existing database may be opened with the commands: (MOE | File | Open) or (DBV | File | Open). Copyright © 2006 Chemical Computing Group, Inc.

78 Exercise: Opening a MOE Database Viewer (cont.)
MOE Overview Exercise: Opening a MOE Database Viewer (cont.) Left-Diagonal drag on a molecule cell to enlarge it. Middle-drag in the molecule cell to rotate the view. XY Rotate Enlarge Molecule View: Left Diagonal Drag on Molecule Cell Middle Drag: Notes: Dragging the middle mouse button over a molecular data cell will rotate the molecule. The same action with the <ctrl> modifier key will zoom in and out on the molecular cell contents. Zoom in/out <Ctrl>Middle Drag: Copyright © 2006 Chemical Computing Group, Inc.

79 Exercise: Database Printing and Tiling
MOE Overview Exercise: Database Printing and Tiling (DBV | File | Print) Click on ‘Tile Molecule Field’. Select ‘Display Entry Number’ and choose the footer to be the field ‘name’. 4. Change Grid: 3x4 You may print selected fields and entries to a printer or else to a file (e.g. PDF or Postscript). You may choose to ‘tile’ the molecule field, so as to visualise the molecule entries more easily, using either 2D or 3D depiction. You may add the details of other fields to the layout, e.g. names, physical properties or descriptors. This feature facilitates rapid communication of results (e.g. with medicinal chemists). Copyright © 2006 Chemical Computing Group, Inc.

80 Exercise: Copying Morphine from the DBV
MOE Overview Exercise: Copying Morphine from the DBV Close the current system in the MOE Window. 2. Copy morphine (entry 1) to the main MOE window by Left-double-mouse click in the mol field 3. Select ‘Clear Molecular Data’ 4. Render as stick (MOE | Render | Stick) Notes: The molecule from the database should now appear in the MOE Window. Copyright © 2006 Chemical Computing Group, Inc.

81 Exercise: Protonate the nitrogen atom in morphine
MOE Overview Exercise: Protonate the nitrogen atom in morphine Left-click on the nitrogen atom, so that it becomes highlighted. Left-click on the ‘Builder’ button on the RHS of the menu bar. Select +1 for the ionisation state. The nitrogen atom is then protonated. Copyright © 2006 Chemical Computing Group, Inc.

82 MOE Overview Molecular Mechanics Aims to predict the structure and properties of molecules. Uses a Force Field with parameters from known structures Energy Minimization calculates the energy of a molecule and adjusts the structure to obtain a lower energy structure. Predicting short-range steric interactions is easy and accurate Predicting long-range electrostatic interactions and the effect of water is difficult. Flexible molecules may need to be described with an ensemble of conformations. Notes: Molecular mechanics techniques in MOE offer a powerful arsenal of tools for structure-based drug design (SBDD). Potential Functions are used to describe intramolecular and intermolecular interactions, with forcefields parameterised for small molecules (e.g. MMFF94) and also for proteins and nucleic acids (AMBER and CHARMM). Molecular Mechanics is a central feature. Computes the potential energy of the current system. Will return interaction energy between selected and non-selected sets. (energy minimisation) Energy Minimise: Minimise the energy within the current forcefield setting. Molecular Mechanics Energy: Dihedral Energy Plot - for energy plotting one torsion angle at a time. Dihedral Contour Plot - for energy plotting two torsion angles at a time. Potential Control – panel for setting the current forcefield. Semi-empirical methods are also available: MOPAC is used for molecular orbital calculations (e.g. HOMO, LUMO). Self-consistent fields (SCF) may be used also for semi-empirical calculations. Copyright © 2006 Chemical Computing Group, Inc.

83 Potential Energy in MOE
MOE Overview Potential Energy in MOE E = ESTR + EANG + ESTB+ ETOR + EOOP + EELE + EVDW + ESOL Forcefield title Forcefield parameter file Toggle on/off terms in the potential Load different forcefields Adjust non-bonded interaction switching function Adjust electrostatics implementation Notes: A potential energy model, equivalently, a forcefield, assigns a potential energy value to a molecular configuration. The potential energy is a sum of interaction energies: E = Estr + Eang + Estb + Etor + Eoop + Eele + Evdw + Esol + Econ  str - bond stretch energies  ang - angle bend energies  stb - stretch-bend cross term energies  tor - dihedral rotation energies  oop - out-of-plane energies  ele - electrostatic interactions  vdw - van der Waals interactions  sol - implicit solvent electrostatic correction  con - constraint and restraint pseudo-energies The Potential Control panel allows you to choose a forcefield for molecular simulations, to turn on or off terms of the potential energy function. You can control which atoms will interact with each other using the State Scale parameters. The Potential Setup panel is found under Window | Potential Setup (in both the MOE Window and the DBV). The energy E is reported in kcal/mol. Only one electrostatics implementation can be used at once (e.g. Born solvation, distance dependent dielectric or gas-phase). You can choose how many parallel processors are used, up to 4. A value of zero means all processors in a machine, up to a maximum of 4, will be used automatically. Partial charge calculation according to selected potential No. of parallel processor threads to be used Copyright © 2006 Chemical Computing Group, Inc.

84 Supported Forcefields
MOE Overview Supported Forcefields Biopolymers (proteins and nucleic acids) AMBER 89, AMBER 94, AMBER 99, CHARMM 22, CHARMM 27, OPLS-AA Small Molecules MMFF94, MMFF94s, MMFF94x Crystallographic Engh-Huber Carbohydrate PEF95SAC Simple Molecular Modelling Rule Notes: Each forcefield is defined in a separate *.ff parameter file in the $MOE/lib directory. The comment lines in these files have more specifics about the implementation and a complete reference list. Here we provide the *.ff parameter filename for each supported forcefield. CHARMM22 : $MOE/lib/charmm22.ff CHARMM27 : $MOE/lib/charmm27.ff AMBER 89: $MOE/lib/koll89.ff AMBER 94: $MOE/lib/koll94.ff AMBER 99: $MOE/lib/koll99.ff MMFF94: $MOE/lib/mmff94.ff MMFF94s: $MOE/lib/mmff94s.ff MMFF94x: $MOE/lib/mmff94x.ff OPLS-AA: $MOE/lib/oplsaa.ff PEF95SAC: $MOE/lib/pef95sac.ff Engh-Huber: $MOE/lib/engh_huber.ff RULE: $MOE/lib/empirical.ff New forcefields are implemented by creating the appropriate parameter file. The default forcefield in MOE is MMFF94x. Copyright © 2006 Chemical Computing Group, Inc.

85 Exercise: Forcefield Energy Minimizations (1)
MOE Overview Exercise: Forcefield Energy Minimizations (1) 1. First choose an appropriate potential and partial charges in MOE | Window | Potential Setup Click on arrow by Load Select the MMFF94 potential Select ‘Fix Charges’ to assign atomic charges according to the chosen potential 2. Press OK and Close Copyright © 2006 Chemical Computing Group, Inc.

86 Exercise: Forcefield Energy Minimizations (2)
MOE Overview Exercise: Forcefield Energy Minimizations (2) 2. Choose MOE | Compute | Potential Energy System energy components Notes: The MOE Window and the SVL Commands Window should contain something similar to the following: E str ang stb oop tor vdw ele sol res ALL: Potential energy components are also shown in the SVL window Copyright © 2006 Chemical Computing Group, Inc.

87 Exercise: Forcefield Energy Minimizations (3)
MOE Overview Exercise: Forcefield Energy Minimizations (3) Minimizations may be forcefield, or semi-empirical (MOPAC 7) Hamiltonian based Automatically add H’s (and LPs if required) Automatically assign partial charges Force current (R/S) stereochemistry Tether Weight (kcal/mol A2) Notes: The Energy Minimization panel is found under Compute | Energy Minimize. Energy minimization (also referred to as geometry optimization) is used to convert 2D molecular drawings to 3D structures, to adjust the positions of roughly placed atoms and to generate low-energy structures. Geometry optimization usually locates the first relatively stable conformation near the starting position, which is not always lowest energy structure. Thus, geometry optimizations are often followed by conformational search simulations to explore other possible minima. MOE offers a choice of minimization methods. Forcefield based minimization proceeds by a refinement using three algorithms in succession; Steepest Descent, Conjugate Gradient, and Truncated Newton. There is a choice of methods of charge determination. Potential Setup window Copyright © 2006 Chemical Computing Group, Inc.

88 Exercise: Forcefield Energy Minimizations (4)
MOE Overview Exercise: Forcefield Energy Minimizations (4) To minimize the molecule, select (MOE | Compute | Energy Minimize) 3. Use the defaults in the panel and press OK Minimized Morphine Copyright © 2006 Chemical Computing Group, Inc.

89 Exercise: MOPAC Minimization
MOE Overview Exercise: MOPAC Minimization Select (MOE | Compute | Energy Minimize) PM3, AM1 or MNDO Option to plot and view orbitals (HOMO and LUMO) To view HOMO/LUMO orbitals go to (MOE | Window | Graphic Objects) Notes: MOE includes an implementation of the public domain MOPAC7 semi-empirical geometry optimisation package. MOPAC7 optimisations can be fired off from within MOE if the PM3, AM1 or MNDO options are chosen in the Energy Minimization window, instead of Forcefield. Calculation of HOMO and LUMO orbitals is implicit in MOPAC calculations and the option to display these is available. Copyright © 2006 Chemical Computing Group, Inc.

90 Calculating Interaction Potential Energies
MOE Overview Calculating Interaction Potential Energies Close the current system (RHS | Close) Open biotin and its receptor (MOE | File | Open ‘$MOE/sample/mol/biotin.moe and biotin_rec.moe’ Add Hydrogen atoms and compute partial charges (MOE | Compute | Partial charge) Select the ligand. Right click in the main MOE window to get popup panel. Popup | Select | Ligand Choose MOE | Compute | Potential Energy ALL: total system E SEL: selected only E Exercise..! Calculating an Interaction Energy Close the current system and open the files $MOE/sample/mol/biotin.moe and $MOE/sample/mol/biotin_rec.moe. Add Hydrogens to the system (Edit | Hydrogens | Add Hydrogens). Compute the partial charges. (Compute | Partial Charges). Select the biotin ligand using the SE. Calculate the potential energy (Compute | Potential). The MOE Window and the SVL Commands Window should contain the following: E str ang stb oop tor vdw ele sol res ALL: SEL: INT: INT: selected – unselected interaction E Copyright © 2006 Chemical Computing Group, Inc.

91 Exercise: Dihedral Energy Plots
MOE Overview Exercise: Dihedral Energy Plots Plots the energy about a single rotatable bond. Close current system. Open $MOE/sample/mol/biotin.moe Add hydrogen atoms (MOE | Edit | Hydrogens | Add Hydrogens) Open the dihedral energy plot panel: MOE | Compute | Mechanics | Dihedral Energy Plot. Select four consecutive carbon atoms in a dihedral. Notes: The Dihedral Energy Plot evaluates the energy vs. one rotatable bond. The red line in the plot shows where the structure in the MOE Window lies on the dihedral plot. The Attributes button in the plot window can be used to change the look of the curve and to label the axes. Copyright © 2006 Chemical Computing Group, Inc.

92 Exercise: Dihedral Contours
MOE Overview Exercise: Dihedral Contours Plots the energy contours about two rotatable bond. Open the Dihedral Contour prompt (MOE | Compute | Mechanics | Dihedral Contour Plot). Select four consecutive carbon atoms in one dihedral, followed by four consecutive carbon atoms in another dihedral. Notes: The Dihedral Contour Plot allows you to evaluate rotational energy barriers for a pair of dihedral angles in a molecule. Copyright © 2006 Chemical Computing Group, Inc.

93 Forcefield Restraints: Energy terms
MOE Overview Forcefield Restraints: Energy terms The restraint energy is a sum of all the individual restraints: ERESTRAINT = S EDistance + S EAngle + S ETorsion ETorsion EAngle Molecular Mechanics restraints are used to enforce geometric constraints during minimizations and other MM-based simulations. Restraint are achieved by additional energy and force terms in the MM potential equation. The total restraint energy is a sum of all the individual restraints. When restraints are set, their energy and forces are included in ALL MM based calculations. Distance restraints are modeled with: Ed = w max (0, L2 - r2)3 + w max (0, r2 - U2)3 w is the weighting factor, [L,U] is the desired interval (L < U) and r is the separation (angstroms). Angle restraints are modeled with: Ea = 100w max(0, cos a - cos L) w max(0, cos U - cos a)3 w is the weight, a is angle (measured in radians) and [L,U] is the desired interval. (L<U). Dihedral restraints are modeled with: Et = 10000w (1 - cos max(0,d - L)) w (1 - cos max(0,U - d))3 where w is the weight, d is the dihedral angle (in radians) and [L,U] is the desired interval. If L is less than or equal to U then the interval is assumed to contain 0.5(L+U) otherwise the interval is assumed not to contain the midpoint. EDistance When restraints are set, their energy and forces are included in ALL MM based calculations. Copyright © 2006 Chemical Computing Group, Inc.

94 Creating Forcefield Restraints
MOE Overview Creating Forcefield Restraints Restraints are created from the MOE | Edit | Potential | Restrain command. The type of restraint and the parameters are set in the following CLI prompters. ‘Create’ must be pressed to create the restraint. EDistance = ( max (0, L2 - r2)3 + max (0, r2 - U2)3 ) * w EAngle = (max(0, cos a - cos L)3 +  max(0, cos U - cos a)3 ) * 100 w To create restraints, choose MOE | Edit | Potential | Restrain in the MOE Window. The prompt appears in the CLI of the MOE Window. The Targets represent the lower (L) and upper (U) target values for each restraint; these must be specified before a restraint can be created. The Weight value represents the proportion by which the potential energy is increased when values stray from the target. Notes: Restraints are saved with the molecule file. Restraints are created with the CLI prompt. If you wish to cancel creation of a restraint, press the ‘Esc’ key. Angle and dihedral restraint targets are specified in degrees. ETorsion = ( (1 - cos max(0,d - L))3 + (1 - cos max(0,U - d))3 * 10000w One-line CLI Prompt menus occupy the SVL Command Line at the top of the window. Press (Esc) to exit the prompts. Copyright © 2006 Chemical Computing Group, Inc.

95 Exercise: Creating Forcefield Restraints
MOE Overview Exercise: Creating Forcefield Restraints To create a distance restraint open (MOE | Edit | Potential | Restraint). Select the acid oxygen and a hydrogen alpha to it. Set the Target Limits as (L = 3.0, U = 3.5, w = 1). Press Create. Similarly, create an angle restraint (L = 1150, U = 1350 , w = 1) between the carboxylate C and the O and H atoms shown here. Note: The restraints drawn in the minimized structure will show the new optimized quantities. Minimized with restraints 3. Minimize the structure (Compute | Energy Minimize). Copyright © 2006 Chemical Computing Group, Inc.

96 The Tethers and Restraints Panel
MOE Overview The Tethers and Restraints Panel The Tethers and Restraints panel (Window | Potential Setup | Restraints) can be used to manage and edit current restraints. Toggle ‘Restraints’ to display restraints Edit selected restraint. Press ‘Apply’ to institute changes. List of current restraints The Meters and Restraints panel displays the list of current meters and restraints in the system. This panel allows you to see the values of the meters and restraints, to select or delete any meter or restraint, and to modify the weights or target values of restraints. Note, however, that you cannot create meters or restraints from this panel. To open the Meters and Restraints panel, use MOE | Window | Meters and Restraints. The panel shows meters and restraints separately, depending on which of the buttons at the top of the panel has been pressed: Press Meters to display the list of currently measured meters. Press Restraints to display the list of current restraints in place. The Weight and Target values apply to restraints only. The Target values restrain the geometric property (bond distances in angstroms, bond angles and dihedrals in degrees) while the weight factors determine the strength of the restraints relative to the total energy of the molecule. Once the target and weight values have been edited, you have to press the Apply button or Return for the changes to take effect. Delete selected restraints Copyright © 2006 Chemical Computing Group, Inc.

97 Exercise: Removing Restraints
MOE Overview Exercise: Removing Restraints Open the Tethers and Restraints panel (Window | Potential Setup | Restraints). Delete all the current distance and angle restraints. Re-minimize the molecule (Compute | Energy Minimize). Minimized with restraints Minimized without restraints Copyright © 2006 Chemical Computing Group, Inc.

98 Exercise: Using the GizMOE Minimizer
MOE Overview Exercise: Using the GizMOE Minimizer The GizMOE Minimizer is a minimizer that runs continuously in the background. With biotin in the system, start the GizMOE Minimizer. MOE | GizMOE | Minimizer Left drag to select and move part of the molecule. Then watch how the energy and geometry are automatically updated. <Alt> <Shift> Drag Translate Selected Atoms Only Notes: Selected atoms may be translated by holding <Shift> and <Alt> and dragging the middle mouse button. Make sure you stop running the GizMOE Minimizer if you intend to load a very large system. 3. Turn off the GizMOE Minimizer. Click the Cancel button and choose GizMOE_Minimizer[]. If necessary re-minimize the system (RHS | Minimize) Copyright © 2006 Chemical Computing Group, Inc.

99 Conformational Searching
MOE Overview Conformational Searching Generation of different conformations of a molecule or a complex is very useful for drug design. Conformational search methods available in MOE Systematic Conformational Search Stochastic Conformational Search Conformational Database Import Molecular Dynamics Notes: Although geometry optimization is a very useful tool, it is often necessary to find many different conformations of a molecule or a molecular complex. MOE contains several methods to perform conformational searches and tools for analyzing collections of conformations. All of MOE’s tools for conformational searching output their results to a MOE database, with 1 entry per conformation. The conformation analysis tools in MOE also rely on the MOE database. The supported search methods are as follows: Systematic Conformational Search: An exhaustive search of torsional space Stochastic Conformational Search: Random sampling of conformational minima. Conformational Database Import: Used for automatic generation of fragment-based conformations upon import of molecular databases. Also available in the Simulations menu is; Molecular dynamics: NVE, NVT, NPT, NPH ensemble sampling. Copyright © 2006 Chemical Computing Group, Inc.

100 Stochastic Conformational Search
MOE Overview Stochastic Conformational Search Random sampling of local minima on the potential energy surface E 1. Perturb geometry EnergyCutoff 2. Minimize Notes: The Stochastic Conformational Search method generates conformations by randomly sampling local minima of the potential energy surface. This method is similar to the RIPS method [Ferguson 1989] which generates new molecular conformations by randomly perturbing the position of each coordinate of each atom in the molecule by some small amount, typically less than 2 angstroms, followed by energy minimization. The Stochastic Conformational Search method in MOE is similar in spirit except that it is based upon random rotations of bonds (including ring bonds) instead of Cartesian coordinate perturbation. Unlike the Systematic Search, the minimization step inherent to the Stochastic Conformational Search simulation makes it difficult to locate conformers that do not lie at potential energy minima. However, Stochastic Search is a fast and powerful method for locating conformational minima for large flexible systems (rings and chains) with many chiral centers. The Stochastic Search panel is found under MOE | Compute | Conformations | Stochastic Search. E0 Torsion Space Copyright © 2006 Chemical Computing Group, Inc.

101 Stochastic Conformational Search Panel
MOE Overview Stochastic Conformational Search Panel Conformation Generation: Output database Randomly: Invert chiral centers Conformation Minimization: Rotate torsions Perturb xyz coordinates Notes: Search Parameters: Chiral Inversion: Randomly invert unconstrained chiral centers. Bond Rotation: Apply random dihedral angle rotation. The Mode controls the dihedral distribution. Dihedral Minimization: Minimization in dihedral coordinates to relieve bad non-bonded contacts. Cartesian Perturbation: Apply random perturbation to atomic coordinates prior to Cartesian coordinate minimization. The perturbation is limited to the value specified in Delta. Cartesian Minimization: Perform minimization in Cartesian space until RMS Gradient falls below RMS Gradient text field to the right. Energy Cutoff: Discard conformations with energy greater than the minimum energy generated plus this value. Conformation Limit: Specifies the limit on the resulting number of conformations. Failure Limit: Number of failed contiguous attempts to generate a new conformation needed terminate search. Iteration Limit: Specifies the maximum number of attempts to generate a new conformation (independent of the novelty of each generated conformation). RMS Tolerance: Conformations with heavy-atom RMSD less than specified value are considered duplicates. Copyright © 2006 Chemical Computing Group, Inc.

102 Systematic Conformational Search
MOE Overview Systematic Conformational Search Exhaustive incremental dihedral rotation search E Cutoff Notes: The Systematic Conformational Search exhaustively searches the conformational space of a molecule by rotating about each rotatable bond. You may specify the bonds to be rotated and the range of rotation angles to be explored. The Systematic Search panel is found under MOE | Compute | Conformations | Systematic Search. With the Energy Minimize Resulting Conformations option OFF, the only structure rejection criterion is the VDW cutoff for bad contact between atom pairs. Such a search can produce a complete search with not just minima, but also transition and intermediate structures; this may be useful if the active conformation of a complexed molecule does not coincide with a minimum energy conformational of the non-complexed structure. With the Energy Minimize Resulting Conformations option ON, each structure will be minimized and an RMSD test applied to remove duplicates. E0 Torsion Space Copyright © 2006 Chemical Computing Group, Inc.

103 Systematic Conformational Search Panel
MOE Overview Systematic Conformational Search Panel Add/Remove dihedrals from list Set dihedral increment Output Database List of bonds to undergo rotation Minimise structures Notes: Rotation Bonds: List of bonds to undergo rotation; <Ctrl>-click to clear the current list selection. Select Atoms: Selects the atoms of all highlighted bonds in the panel. Add: Any bond between two selected atoms in the MOE Window will be added to the list. Remove: Removes highlighted bonds from the list. Step: Sets the dihedral angle increment for each bond selected in the Rotation Bonds list. VDW Contact: A conformation is excluded if any pair of atoms has a VDW contact energy greater than the given value (in kcal/mol). Database: Name of molecular database file for generated conformations. The default name is csearch.mdb. Minimization: If Energy Minimize Resulting Conformations is ON, MOE will energy minimize the resulting conformations, remove duplicates based on RMSD. RMS Gradient: Energy minimization stops when the RMS gradient falls below this value. RMS Distance: The Root Mean Square Distance used to detect duplicate (in angstroms). Cutoff: Energy minimized conformations will be discarded if their potential energy is greater than Emin + Cutoff, where Emin is the lowest energy among the minimized conformations. Copyright © 2006 Chemical Computing Group, Inc.

104 Exercise: Systematic Conformational Searching (1)
MOE Overview Exercise: Systematic Conformational Searching (1) Close the current system (RHS | Close) Open up the MOE file for the molecule built earlier (MOE | File | Open ‘my_first_molecule.moe’). Perform a systematic search on this molecule using the default options (MOE | Compute | Conformations | Systematic Search) Left-Drag in DBV molecule cell to view structures. Notes: When the search is started, a database viewer window is opened which contains the conformations generated by the search. Enlarge Molecule View: Left Diagonal Drag on Molecule Cell Copyright © 2006 Chemical Computing Group, Inc.

105 Exercise: Systematic Conformational Searching (2)
MOE Overview Exercise: Systematic Conformational Searching (2) Open (DBV | Compute | Descriptors). Enter ‘Energy’in the Filter field. Select the descriptor (Left mouse click once) “E Potential Energy” and press OK. Notes: Since we did not toggle on the energy minimization option in the systematic conformational search panel, no strain energies are listed in the database. We can automatically calculate the strain energy of each conformation using the QuaSAR-Descriptor panel in the DBV. Copyright © 2006 Chemical Computing Group, Inc.

106 Exercise: Sorting and Selecting Conformers
MOE Overview Exercise: Sorting and Selecting Conformers 2. Left double click on the lowest energy conformer in the mol field to copy to the MOE Window. 1. Position the mouse over the E Field. Right click to use Field Header popup to Sort UP on energy. Copyright © 2006 Chemical Computing Group, Inc.

107 Superposing Conformations
MOE Overview Superposing Conformations Database to perform calculations on Mol field to perform calculations on Measurements to perform on database Superposition of conformers in database Notes: Superposition The Superposition section of the panel refers to superposing the conformations in the database with the sample conformation presently in MOE. Align: Specifies which atoms to use in the superposition: All Atoms: Use all atoms in the loaded conformation. Selected Atoms: Use selected atoms only. Heavy Atoms: If on, superposition is with respect to heavy atoms only. Molecule Field: Determines how the results of the superposition are written to the database with respect to the Molecule Field specified in the upper section of the panel: Output No Structures: Saves only the RMSD results in the database, not the molecular structures resulting from the superposition. Make sure, in this case, to name the RMSD field. Overwrite Current Field: Overwrites current Molecule Field with the superposed structures. Create New Field: Creates a new molecule field in which to save the superposed structures. Enter the name of the new field in the adjoining text area. RMSD Field: Name of the database field which will contain the measured RMSD value between each aligned structure and the sample conformation. Superpose: Press Superpose to superpose each structure on to the atoms in the sample conformation. The resulting structures and RMSD values are written to the database. Auto-Label atoms by element and number Copyright © 2006 Chemical Computing Group, Inc.

108 Exercise: Superposing Conformations
MOE Overview Exercise: Superposing Conformations Left mouse drag to select the methyl substituted pyridine ring Bring up the Conformation Geometries panel. (DBV | Compute | Conformation Geometry…) Change Molecule Field: to Overwrite Current Field. Click on the Selected Atoms buttons. Click on the Superpose button. Copyright © 2006 Chemical Computing Group, Inc.

109 Exercise: Superposing Conformations (cont.)
MOE Overview Exercise: Superposing Conformations (cont.) Shift Left mouse click over a subset of entries (try entries 1 to 5) Use Molecule Cell popup to Copy Selected Entries to MOE Window Observed the superposed conformations Color by chain using (MOE | Popup | Color | Chain) Copyright © 2006 Chemical Computing Group, Inc.

110 Diverse Conformational Subset
MOE Overview Diverse Conformational Subset Open the Diverse Subset panel (DBV | Compute | Diverse Subset). 2. Set the Output Limit to 20. 3. Choose ‘Conformation’ as the selection method. 4. Press OK to start calculation. Notes: A new field $DIVPRIO will appear in the database. The diverse conformers are numbered 1 to the output limit (in this case 20). All other conformers are given a $DIVPRIO value N+1 where N is the number of compounds in the database. Copyright © 2006 Chemical Computing Group, Inc.

111 Exercise: Diverse Conformers Subsets
MOE Overview Exercise: Diverse Conformers Subsets Use Field popup to Sort Up on $DIVPRIO. Copy 20 diverse conformers to MOE with popup. Shift Left click over entries 1 to 20. Position mouse in mol field and use Right mouse button to get Popup. Select Copy Selected to MOE Remember to select Clear Molecular Data Render conformers as stick (MOE | Render | Stick) Copyright © 2006 Chemical Computing Group, Inc.

112 Interactive Superposition
MOE Overview Interactive Superposition Edit | Interactive Superpose is a tool for optimally superposing molecules based on selected point sets. More than two structures may be superposed simultaneously. Notes: At least 3 atoms from each structure must be chosen before the superposition can be performed. Fixed atoms will not move in the superposition. Fixing a reference structure will force all structures to be transformed to the coordinates of the reference. This is a useful when superposing structures on to a ligand bound in an active site. Copyright © 2006 Chemical Computing Group, Inc.

113 Exercise: Interactive Superpose (1)
MOE Overview Exercise: Interactive Superpose (1) Close the current system and open (File | Open) $MOE/sample/mol/opiate_analogs.mdb Select entry 1 and 7 (morphine and heroin). Copy to MOE window If molecules are superposed, separate by Ctl-Left click on an atom of one molecule, to select entire molecule. Separate by moving selected molecule using Shift-Alt-Middle mouse Center the view (RHS | View). Render the structures as ball and stick (Render | Ball and Stick). Hide the hydrogens (Render | Hide | Hydrogens). Initiate superpose (Edit | Superpose). 1 2 3 Copyright © 2006 Chemical Computing Group, Inc.

114 Exercise: Interactive Superpose (2)
MOE Overview Exercise: Interactive Superpose (2) For Set 1 select the indicated oxygens labelled (1) on each molecule Press Set: 2 in the CLI prompt and select the indicated aromatic ring carbons labelled (2) Press Set: 3 in the CLI prompt and select the indicated oxygen atoms directly connected to the benzenes labelled (3) With the minimum 3 point sets specified, the Superpose is possible. Press Superpose to superpose the structures. Pressing Superpose will superpose the structures based on an optimal RMSD. Copyright © 2006 Chemical Computing Group, Inc.

115 Flexible Alignment of Small Molecules
MOE Overview Flexible Alignment of Small Molecules Feature-based alignment of 2 or more molecules Features are pharmacophore-like Stochastic search algorithm employed for flexibility Weighting scheme for features Notes: Often, we know which molecules are active against a particular protein target but have little or no firm knowledge about the structure of that target. There may, however, be some commonality in the accessible geometries of the active molecules that may enable us to derive a design crierion for other (or of course better!) active molecules. MOE contains an application, “Flexible Alignment”, which derives such commonality for 2 or more known active molecules. It uses pharmacophore-like features (H-bond acceptor and donor, aromatic ring centres, etc.) to overlay the molecules, minimising the difference in geometry between the feature sets by flexing the molecules under the influence of a forcefield. Thus the solutions obtained take account both of the feature set geometries and the conformational accessibility of the molecules. The stochastic search algorithm is used to flex the molecules – in each cycle, conformations are randomised, then the molecules are overlaid using the feature sets, and then a cost function which takes account of the feature set geometries and the conformational strain, is minimised. Copyright © 2006 Chemical Computing Group, Inc.

116 Exercise: Flexible Alignment of Opiates (1)
MOE Overview Exercise: Flexible Alignment of Opiates (1) Close the current system (RHS | Close) and import morphine, heroin and demerol (entries 1, 7, 11) from the database $MOE/sample/mol/opiate_analogs.mdb Ensure that the partial charges have been set, using MOE | Compute | Partial Charges. Select one of the molecules using Ctl-Left mouse click on an atom of one molecule and fix it: MOE | Edit | Potential | Fix. Notes: To ensure that the molecules appear separated on the screen, you can left-click on an atom, and then go to Selection | Extend | Chain. With the whole molecule now selected, you can press ‘Shift’ and ‘Alt’ simultaneously and press down the middle mouse button. This will translate the molecule. You may need to press “View” on the RHS button bar to refresh the visualisation appropriately. Copyright © 2006 Chemical Computing Group, Inc.

117 Exercise: Flexible Alignment of Opiates (2)
MOE Overview Exercise: Flexible Alignment of Opiates (2) 6. Choose MOE | Compute | Conformations| Flexible Alignment. Decrease the iteration limit down to 20, instead of 200. 7. Preserve defaults and press OK Notes: The top level box contains choices for alignment mode (see later), output database and some of the parameters for the stochastic search algorithm, such as termination criteria and specification of the energy cutoff window. A second level of parameters can be found by selecting “Settings”. Here we find more stochastic search parameters, and the pharmacophore-like similarity terms and weighting scheme employed by the algorithm. A series of defaults are set here – these have been found to work well in a variety of situations. See P. Labute, C. Williams, M. Feher, E. Sourial, J.M. Schmidt; J. Med. Chem. 44 (2001), Similarity terms and weighting Copyright © 2006 Chemical Computing Group, Inc.

118 Exercise: Flexible Alignment of Opiates (3)
MOE Overview Exercise: Flexible Alignment of Opiates (3) 8. Let the application run to completion. 9. Sorting in S occurs automatically 10. Choose the “best” alignment “Best” may be that with the lowest scoring function value – but take strain into account! Notes: The output columns are U (the TOTAL energy of the aligned molecules), F (the feature-matched scoring function), S (=U+F, the minimised cost function), and their deltas, (i.e. the amount above the global minimum for each part of the function). There should not be too many solutions within the cutoff energy window – due to the stochastic nature of the algorithm, not everyone will obtain identical results. However, the “best” solution (inspect those with the lowest S and U values particularly) should be easily identifiable. In this case, solutions 1 and 2 are virtually identical. Copyright © 2006 Chemical Computing Group, Inc.

119 Exercise: Flexible Alignment of Opiates (4)
MOE Overview Exercise: Flexible Alignment of Opiates (4) 11. Copy the “best” alignment into the MOE Window. - Aligning multiple molecules can be time-consuming; try aligning them one at a time, keeping the earlier alignments fixed. Notes: When aligning many molecules, the number of degrees of freedom goes up enormously and so the alignment process can be time-consuming. One way round this is to align the molecules a few at a time – start with 2, 3 or 4 of them, and when a satisfactory alignment is achieved for them, freeze that alignment using MOE | Edit| Potential | Fix and add the others in batches. MOE | Edit| Potential | Fix may also be useful if you want to keep the coordinate frame of reference AND conformation of one of your aligning molecules unchanged, perhaps if it comes from a crystallographic result. This can in fact allow you to overlay the resultant aligned other molecules on the structure of the target to see if the solutions are plausible. Copyright © 2006 Chemical Computing Group, Inc.

120 Exercise: Rendering of the Flexible Alignment
MOE Overview Exercise: Rendering of the Flexible Alignment Select MOE | Render | Color | Chain. This will colour the chains (i.e. separate molecules) of the flexible alignment. Close the current system (RHS | Close) Close all windows except the main MOE window Copyright © 2006 Chemical Computing Group, Inc.

121 Further Simulation Techniques
MOE Overview Further Simulation Techniques Poisson-Boltzmann electrostatics e.g. analysis of active site in a receptor can reveal the effect of the surrounding residues on the binding properties of a ligand. Solution of the full non-linear PB equation, allowing for different ion classes, radii and partial charges. Molecular Dynamics e.g. use to relax structures and to generate conformational states at a desired temperature and/or pressure (in NPT, NVT, NVE, NPH). Notes: Further atomistic simulation techniques which are of use in drug discovery: Molecular Dynamics: e.g. use to relax structures and to generate conformational states at a desired temperature and/or pressure (in NPT, NVT, NVE, NPH). Molecules may be fixed, or may have relative or absolute constraints (e.g. fixed bond lengths to H atoms, atomic tethers to absolute positions, wall potential to keep atoms or residues within a defined region). Poisson-Boltzmann Electrostatics: e.g. analysis of active site in a receptor can reveal the effect of the surrounding residues on the binding properties of a ligand. Solution of the full non-linear PB equation, allowing for different ion classes, radii and partial charges. Copyright © 2006 Chemical Computing Group, Inc.

122 Further Simulation Techniques
MOE Overview Further Simulation Techniques Docking Flexible ligands and a rigid receptor. The poses may be constrained to fit a pharmacophore query. Affinity dG scoring is used to estimate the enthalpic contribution to the binding free energy of hydrogen bonding, ionic, metal ligation and hydrophobic interactions. Notes: Another important simulation method in MOE, which is very important in SBDD: Docking: Flexible ligands and a rigid receptor. The poses may be constrained to fit a pharmacophore query. Affinity dG scoring is used to estimate the enthalpic contribution to the binding free energy of hydrogen bonding, ionic, metal ligation and hydrophobic interactions. Copyright © 2006 Chemical Computing Group, Inc.

123 Introduction to Database Viewer Analysis
MOE Overview Introduction to Database Viewer Analysis Used for: Cheminformatics QSAR Clustering Similarity Search Diverse Subsets Fingerprints Library Generation/Design Ph4 applications Output for Conformation search Dynamics Flexible alignment Docking Washing / Processing The MOE Database Viewer DBV is the main launch point for MOE’s QSAR and small molecule database applications. These include:  Histogram, 2D and 3D data plotting. Recording, viewing and analyzing conformational search results. QSAR descriptor calculation. Cluster analysis and Principle component analysis. Tools for building QSAR models using Linear Regression, Binary-QuaSAR and Recursive Partitioning. Substructure searching based on SMILES and SMARTS strings. Combinatorial library enumeration and analysis. Copyright © 2006 Chemical Computing Group, Inc.

124 Exercise: Opening a MOE Database Viewer
MOE Overview Exercise: Opening a MOE Database Viewer (File | Open) Select the file $MOE/sample/mol/blood_brain.mdb. Open in a database viewer (Open in Database Viewer). Save a local copy (DBV | File | Save ‘bbb.mdb’) Notes: A new MOE database may be created with the commands: (MOE | File | New | Database) or (DBV | File | New). An existing database may be opened with the commands: (MOE | File | Open) or (DBV | File | Open). Copyright © 2006 Chemical Computing Group, Inc.

125 Exercise: Calculating Descriptors
MOE Overview Exercise: Calculating Descriptors 1. Open the QuaSAR-Descriptor panel (DBV | Compute | Descriptors). 2. On the Filter line, type TPSA. Left click once on TPSA in the panel to select. 3. Repeat to select Weight, logP(o/w), and MR 4. Press OK and descriptors will be calculated into the database Notes: Three new fields, TPSA, mr, and logP(o/w)will be calculated in the database. You must have a read/write copy of the database to do this; if you do not, save a local copy of the database to use for this exercise. Descriptor Filter Copyright © 2006 Chemical Computing Group, Inc.

126 Exercise: Sort by Activity
MOE Overview Exercise: Sort by Activity Sort in descending order of logBB 1. Open the Sort Database panel (DBV | Compute | Sort). 2. Select Field: “logBB” 3. Enable “Descending” 4. Press OK Copyright © 2006 Chemical Computing Group, Inc.

127 Exercise: Plotting Data
MOE Overview Exercise: Plotting Data Open the DBV Plot window (DBV | Display | Plot). Select logBB as the numeric value to plot. Use the Right button in the plot area to compute the range with the DBV Plot popup. Copyright © 2006 Chemical Computing Group, Inc.

128 Mouse Actions in the DBV Plot Window
MOE Overview Mouse Actions in the DBV Plot Window Entry Selection is reflected in the DBV and the DBV Plot window <Shift> Drag: XY Translate Plot Drag on axis: Selection Range <Ctrl>Drag: Zoom in/out of Plot Left Click: Select points individually Drag: Selection Box Copyright © 2006 Chemical Computing Group, Inc.

129 Exercise: Select actives
MOE Overview Exercise: Select actives Select compounds with logBB > 0 Select active compounds by using Left mouse drag in Plot:Display for all entries where logBB > 0. Notice selected entries are updated automatically in the database viewer Copyright © 2006 Chemical Computing Group, Inc.

130 Exercise: Hide Inactives
MOE Overview Exercise: Hide Inactives Hide all compounds with logBB < 0 Since all compounds with logBB > 0 are selected, go to (DBV | Entry | Hide Unselected entries) 2. Use the Right button in the plot area to compute the range Copyright © 2006 Chemical Computing Group, Inc.

131 Exercise: Look at active compounds
MOE Overview Exercise: Look at active compounds Launch database browser by going to (DBV | File | Browser) Select Subject:mol (2D) for depicted mode Use forward/backward triangles to navigate Copyright © 2006 Chemical Computing Group, Inc.

132 Exercise: Plot descriptor and activity relationship
MOE Overview Exercise: Plot descriptor and activity relationship Show all entries (DBV | Entry | Show All Entries). Start the database correlation plot prompt (DBV | Compute | Analysis | Correlation Plot…). 3. Pick ‘TPSA’ and ‘logBB’ to plot along X and Y. Notes: The correlation plot displays the scatter plot with the regression statistics located at the top of the window. The plot attributes may be changed by pressing the Attributes button. Adjustable attributes include: General attributes - Plot title, legend, ticks, axis and grid. Axis attributes - Title, range. Series attributes - Number, title, line style and color, marker style. Copyright © 2006 Chemical Computing Group, Inc.

133 Exercise: Show relationship between all fields
MOE Overview Exercise: Show relationship between all fields Start the database correlation matrix prompt (DBV | Compute | Analysis | Correlation Matrix…). Press on TPSA/logBB to get same correlation plot Copyright © 2006 Chemical Computing Group, Inc.

134 Exercise: Select actives
MOE Overview Exercise: Select actives Select points in the plot: Drag: Selection Box Entry Selection is reflected in both the DBV and Correlation Plot Notes: To select values in the plot, drag a selection box around data points using the left mouse button. Entries are selected in the plot and Database Viewer. The inverse is also true. Selecting entries in the Database Viewer automatically selects them in the Correlation Plot panel. To deselect entries, use the Clear Entry Selection in the Entry menu or in the Entry Popup menu. Use the Attributes menu to change look of the plot Copyright © 2006 Chemical Computing Group, Inc.

135 Exercise: Show relationship of actives with logP(o/w)
MOE Overview Exercise: Show relationship of actives with logP(o/w) Hide inactives, go to (DBV | Entry | Hide Unselected entries) Start the database correlation plot prompt (DBV | Compute | Analysis | Correlation Matrix…). Press on logP(o/w) / logBB to get correlation plot Copyright © 2006 Chemical Computing Group, Inc.

136 Exercise: Show clustering of actives and inactives
MOE Overview Exercise: Show clustering of actives and inactives Show all entries (DBV | Entry | Show All Entries) Open 3D Plot (DBV | Compute | Analysis | 3D Plot) Set X to “Weight”, Y to “TPSA”, Z to “logP(o/w)” Set activity to “logBB” Set Threshold to 0 Press Plot Enlarge points using (MOE | Render | Ball and Line) Copyright © 2006 Chemical Computing Group, Inc.

137 Pharmacophore Overview
MOE Overview Pharmacophore Overview Aim: to find chemically unrelated molecules which share molecular features Take an active molecule. Annotate possible PH4 features Create a query with these features Take conformations of a set of diverse molecules. Annotate with PH4 features Find hits which match the query. HB Acceptor Aromatic Copyright © 2006 Chemical Computing Group, Inc.

138 Compute | Conformations | Pharmacophore Elucidation
MOE Overview Compute | Conformations | Pharmacophore Elucidation Objective Starting from single conformations of active and inactive compounds, sample conformations on the fly and automatically extract maximum common Ph4 pattern which selectively recognizes active features. Text report Output database Ligand database Activity threshold: binary or no activity Specification of conformational method Selection of Ph4 schemes that can be stored and loaded Feature list and feature properties Modification of features / rules Pharmacophore search parameters Parameters for structure alignment Copyright © 2006 Chemical Computing Group, Inc.

139 Exercise: Pharmacophore Elucidation I
MOE Overview Exercise: Pharmacophore Elucidation I The Elucidator will try to identify popular Ph4 patterns from sets of unaligned molecules. To validate the performance of the Elucidator, we will start with an example where we know the “optimal” result (aligned by nature in X-ray protein structures): Open Elucidator panel in (MOE | Compute | Conformations | Pharmacophore Elucidator) Choose an output database name (default: ph4elucidate.mdb) 3. Browse to select as Input Database: $MOE/sample/mol/1RO6_ligands.mdb This has 7 ligands from pdb structures Switch the Conformations setting to Bond Rotation. Leave the Activity Field as “All Active” since all ligands are active in this example (otherwise you would select the activity/inactivity threshold here) Remain with the default Ph4 scheme (CHD) and click OK. Copyright © 2006 Chemical Computing Group, Inc.

140 Pharmacophore Elucidation II
MOE Overview Pharmacophore Elucidation II The output database looks like… Conformations of Ph4 alignment Active molecules Separation of actives/inactives Accuracy of actives Accuracy of inactives Query features: D/A = heavy atom Don/Acc d/a = projected Don/Acc H = Hyd/Aro m = Metal +/- = Cation/Anion Alignment score Query information for DB Browser Number of features of specific type Probability by chance Total Number of features Copyright © 2006 Chemical Computing Group, Inc.

141 Exercise: Pharmacophore Elucidation III
MOE Overview Exercise: Pharmacophore Elucidation III The output database is sorted by ascending overlap (alignment) score. 6. Use (DBV | File | Browser) to examine each Ph4 alignment. Note the modified view of the browser while displaying the results. You may want to modify input parameters in your elucidator calculation interface if you are not satisfied with the quality of the results or you may directly edit the underlying queries to further refine the results. You may want to save the current Ph4 query or modify the features of a given entry. Double-clicking in the query cell in the Database Viewer will launch the Ph4 Query Editor. Edit in the Database Browser brings up the Ph4 Query Editor. Copyright © 2006 Chemical Computing Group, Inc.

142 4. The SVL Commands Window
MOE Overview 4. The SVL Commands Window SVL is a powerful language designed to allow you to customize MOE and extend MOE with your own functions Open the SVL Commands Window with (RHS | SVL) Notes: What is SVL (Scientific Vector Language)? Command language of MOE. Script language of MOE. Applications programming language of MOE. Characteristics of SVL: High-level language - vector based-Interactive and compiled (byte code). Very concise code (10 times less than C or Fortran). High-performance. Inherently portable. MOE is a hybrid byte-code / native code system: Base system is written in C (native code - executable only). Applications are written in SVL (byte code - source code). Port of base system automatically ports SVL programs. Collection-oriented (vector) operations deliver efficient and concise programs (small line count). Copyright © 2006 Chemical Computing Group, Inc.

143 Exercise: SVL Commands Window
MOE Overview Exercise: SVL Commands Window SVL commands are prefixed in the text with svl>. For example, enter 3+4 in the SVL Commands Window: svl> 3+4 Press Enter 7 2. SVL commands can be used to open menus and build molecules from SMILES strings For example, build methane by entering svl> sm_Build ‘C’ Notes: The SVL Commands Window (CLI): The CLI is a place to type commands and/or evaluate SVL expressions. Several MOE windows contain a CLI (Command Line Interpreter) for entering SVL commands. A history of commands is maintained and accessed with the arrow keys. The Tab key is used for file name completion or function name completion. The SVL Commands Window is a CLI as well as a scrolling text window. Many programs output results to the Commands Window so you should become accustomed to referring to it. Copyright © 2006 Chemical Computing Group, Inc.

144 Basic SVL windows in MOE
MOE Overview Basic SVL windows in MOE Text Editor (TED) ASCII file / SVL program editor Modules & Tasks Manager Program control / Source Code Notes: SVL Text Editor Window-based text editor accessible from within MOE. Can be used to directly load or run SVL programs. Files ending in .svl are automatically recognized as SVL code. Color-coded text to make reading SVL code easier. Edit Function command used to locate the file in which an SVL function is found (if source code is available). Any other text editor can be used to write SVL programs. Modules and Tasks window A task is an execution thread; A module is a compiled SVL code file (containing functions). The Modules and Tasks Manager displays all loaded modules as well as all running tasks. Unloading system modules may have undesirable results; e.g., menus don’t work. Restart MOE. SVL Crash History Gives a source-level execution trace for the last error generated from an SVL task. Can be used to open a text editor at the line of code that caused the problem. Crash History Source-level error trace-back Copyright © 2006 Chemical Computing Group, Inc.

145 Appendices MOE Overview
Copyright © 2006 Chemical Computing Group, Inc.

146 Forcefield File alkane.ff: Atom Typing Block
MOE Overview Forcefield File alkane.ff: Atom Typing Block #moe:forcefield #comment lines title ALKANE disable oop stb itortype CT C 'sp3 C'type HC H 'H attached to alphatic C'[rules] # TYPE ASSIGNMENT RULES CT match '[CX4]‘ HC match '[#1]C‘ Notes: An atom type is an equivalence class of atoms, for instance, those of a given geometry or those bonded to certain elements. Each atom type has its own associated model parameters, which are obtained empirically by fitting to experimental or to quantum mechanical values. The first step in building a model is the definition of atom types. Atom types are listed at the top of the parameter file. Each atom type describes an atom of a given element in a particular context. Each type must be unique, thought two or more atom types may refer to the same element. Each atom type definition consists of a single line containing the type symbol, the underlying element and a textual description of the type. MOE uses an automatic method of assigning atom types to atoms during calculations. This automatic method uses substructure searching and pattern matching to detect the context in which a particular atom is found. The substructure search is controlled by the Matching Rules section of the parameter file. Please see the MOE manual for more information. Copyright © 2006 Chemical Computing Group, Inc.

147 Forcefield File alkane.ff: Bond Stretch Block
MOE Overview Forcefield File alkane.ff: Bond Stretch Block [str] # BOND STRETCH #code T1 T2 LEN K2 K3 K4 bci # * CT CT * CT HC Copyright © 2006 Chemical Computing Group, Inc.

148 Forcefield File alkane.ff: Angle Bend Block
MOE Overview Forcefield File alkane.ff: Angle Bend Block [ang] # ANGLE BEND ang-function angle #CODE T1 T2 T3 ANG K2 K3 K4 # * CT CT CT * CT CT HC * HC CT HC Copyright © 2006 Chemical Computing Group, Inc.

149 Forcefield File alkane.ff: Torsion Block
MOE Overview Forcefield File alkane.ff: Torsion Block [ptor] # proper torsion # T1 T2 T3 T4 V1/2 V2/2 V3/2 V4/2 V5/2 # * CT CT CT CT * CT CT CT HC * HC CT CT HC Copyright © 2006 Chemical Computing Group, Inc.

150 Forcefield File alkane.ff: Electrostatics Block
MOE Overview Forcefield File alkane.ff: Electrostatics Block [nonbonded] # nonbonded information ele-dielectric 1 # dielectric+distance dependent flag ele-buffer # electrostatic buffering ele-scale # 1-4 interaction scaling ele-charge-fcn alkane # svl fcn to compute charges Copyright © 2006 Chemical Computing Group, Inc.

151 Forcefield File alkane.ff: VDW Block
MOE Overview Forcefield File alkane.ff: VDW Block vdw-scale14 1  [vdw] # VDW PARAMTERS ---- #T1 T2 R EPS m n # CT CT CT HC HC HC Copyright © 2006 Chemical Computing Group, Inc.

152 Visualization Setup: Coloring
MOE Overview Visualization Setup: Coloring MOE | Render | Setup… Set colors of objects Press Apply to institute changes Restore defaults Save new settings as defaults Copyright © 2006 Chemical Computing Group, Inc.

153 Visualization Setup: Dimensions
MOE Overview Visualization Setup: Dimensions Protein Ribbon dimensions Atom and Bond dimensions Copyright © 2006 Chemical Computing Group, Inc.

154 Visualization Setup: Lighting and Projection
MOE Overview Visualization Setup: Lighting and Projection Copyright © 2006 Chemical Computing Group, Inc.

155 SVL and MOE-batch MOE/batch Terminal-style interface (no GUI).
MOE Overview SVL and MOE-batch MOE/batch Terminal-style interface (no GUI). SVL commands entered at prompt. Used for scripting long tasks and automating procedures. Running MOE/batch One of MOE's significant features is that it also runs in terminal mode, a non-graphical version of the MOE software called MOE/batch. In batch mode, you can issue all the SVL functions (except, of course, graphical and window-generating commands) as you would from the SVL command line in the graphical version of MOE. MOE/batch is typically used for background calculations that do not require a graphical interface. We will assume that the MOE root directory is /usr/local/moe on UNIX systems and c:\moe on Windows systems. To run MOE/batch on a UNIX system type: user% /usr/local/moe/bin/moebatch in a terminal shell. If you have put /usr/local/moe/bin into the PATH environment variable then you must set the MOE environment variable to /usr/local/moe. To run MOE/batch in a Windows system, open an MS-DOS Prompt window and type: user% c:\moe\bin-i4w9\moebatch In any event, when ready for an SVL command, MOE/batch will prompt with moe>: moe> If the moe> prompt does not appear after a few seconds, then there is a problem with the installation. You can exit MOE/batch with moe> Quit[] Copyright © 2006 Chemical Computing Group, Inc.


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