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The Main MOE Windows SVL Commands Window (CLI) Custom SVL, interactive scripting, session logging Sequence Editor (SE) Protein bioinformatics, homology.

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Presentation on theme: "The Main MOE Windows SVL Commands Window (CLI) Custom SVL, interactive scripting, session logging Sequence Editor (SE) Protein bioinformatics, homology."— Presentation transcript:

1 The Main MOE Windows SVL Commands Window (CLI) Custom SVL, interactive scripting, session logging Sequence Editor (SE) Protein bioinformatics, homology modeling, sequence analysis 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

2 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

3 Intro 2: The Sequence Editor Used for: Protein bioinformatics Sequence alignment Homology searching Homology modeling Target family analysis RCSB download Consensus modeling PDB searching

4 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

5 Intro 4: The SVL Commands Window Used for: Custom SVL Interactive scripting Session logging

6 Layout of Course 1. Main MOE Window: a) Opening/saving files b) Building molecules c) Rendering 2. Introduction to the Sequence Editor 3. Introduction to the Database Viewer a) Basics of molecular mechanics and conformational searching b) Basics of cheminformatic analysis with the Database Viewer 4. Comments on SVL

7 1. Structure of the MOE Window Main Menu Commands SVL Command Line 3D Rendering Area Task Cancel Button RHS Button Bar Footer Pager Bar Popup menu

8 MOE Menu Command Conventions (Render | Backbone | Color | Chain Color) or (MOE | Render | Backbone | Color | Chain Color) Commands from the MOE Window are preceded by MOE or ()

9 Mouse Conventions in MOE General Mouse Actions 3-Button Mouse – 2-Button Mouse Mapping LEFT - Selecting objects, menu commands MIDDLE - Rotating, translating moving objects RIGHT - SE and DBV Popup menus Press and releasekey

10 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.

11 Opening Files in MOE – (File | Open) Recent Directories List Operations to Perform on selected file(s) Enforce File Type Change Working Directory (CWD) Current Path/ Directory Open file in text editor Open file into MOE Directory/ File List Path Text Field ‘.. ’ go up a Directory

12 Exercise: Opening a File 3.Find the file $MOE/sample/mol/ 4.Open MOE file into the MOE Window by either: a)Selecting the file and clicking OK or Open in MOE. b)Double left-clicking on the filename. 1.Open the File Open panel (File | Open). 2.Use the pull-down menu to switch to the $MOE/sample/mol directory.

13 Exercise: Opening a File (cont.) 5.Center the View (Render | View or RHS | View). 6.Render the molecule in stick mode (Render | Stick).

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

15 Exercise: Render molecule 1.MOE | Render | Draw | Hydrogen Bonds 2.Mode | Ball and Stick 3. Label | Name Render as ball and stick, label all atoms by name, and show H-Bonds 4. Label | Clear

16 Exercise: Saving a picture (1) 3. Click on Set CWD to set as the new working directory 2. Click on MkDir to create a new directory called ‘course’ 1. Choose MOE | File | Save

17 Exercise: Saving a picture (2) 4.Choose Save ‘Picture ’ 5.Enter the filename ‘sulph_quin.png’ 6.Choose Format ‘PNG’ 7.Finally click on Save

18 Rendering 2D Depicted Molecules 1. MOE | Edit | Automatic | Depict as 2D 2.Press ‘Export Bitmap’ to save picture as ‘sulph_quin2.png’ 3.Press OK 4.Press Close

19 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) Drawing Molecular Surfaces

20 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

21 Exercise: Drawing Molecular Surfaces (1) 1.Draw a surface around the inhibitor by first choosing (MOE | Compute | Surfaces and Maps) using the default options 2.Press Apply

22 To print the current MOE 3D window choose MOE | File | Print... Printer or Postscript file Header Landscape/Portrait Footer Exercise: Outputting the system… to the printer

23 Exercise: Outputting the system… to various formats 1.Save the current MOE 3D window. MOE | File | Save Enter filename to save ‘’ 3.Choose Save: Molecule and To save surface, select Graphics:All 4. Click on Save

24 Exercise: Close System and Open Builder 1.Close the current system (MOE | RHS | Close) 2. Open the Builder (MOE | RHS | Builder)

25 The Molecule Builder Edit or Add Element Enter Fragment SMILES string Edit: 1.Compound Name 2.Bond Length 3.Bond Angle 4.Torsion Edit Ionization State Fragment substitution buttons Other atom types, including dummy atom at centroid Edit Chirality Library of functional groups Undo button

26 Exercise: Build a molecule Select C Press Select C Press

27 Shift-select 2 C Press Shift-select 2 CPress Exercise: Build a molecule (cont.)

28 Select HPress Press 4 times Exercise: Build a molecule (cont.) Select H

29 Press Exercise: Build a molecule (cont.) Press Select H Press Deselect H

30 Exercise: Energy Minimize RHS | Minimize

31 Save Molecule 1.Save the current MOE 3D window as a MOE file. MOE | File | Save... Enter filename to save ‘’ Save ‘Molecule’ Choose Format ‘MOE’ 2. Press Save

32 Protein and Carbohydrate Builders MOE | Edit | Build | Protein or SE | Edit | Protein Builder MOE | Edit | Build | Carbohydrate

33 Selecting Atoms with the Left Mouse Button Left Drag: Selection Box - Left Click: Auto-extend selection to residue - Left Click: Add to / toggle atom selection Left Click: Select atoms one at a time Note on - Left Click: There is only one residue in the built molecule, so the whole molecule will be selected. This will be revisited later.

34 Exercise: Selecting Atoms with the Left Mouse Button 1.Use Left-Click to select atoms one at a time. 2.Use Left-Drag to draw a selection box. 3.Use - Left Click extend/toggle atom selections. 4.Use - Left Click to select entire residues. 5. Left-mouse click in empty space to de-select any atoms.

35 Exercise: Fixing/Unfixing Atoms (Edit | Potential | Fix / Unfix) Fixing atoms : 1.Left mouse drag to select the atoms to be fixed. 2.Fix the atoms with the command (Edit | Potential | Fix). Fixed Atoms do not move until unfixed. Unfixing atoms : 1.Select the atoms to be unfixed. Use (Selection | Potential | Fix) to select all the fixed atoms. 2.Unfix the atoms with the command (Edit | Potential | Unfix). Once unfixed the atoms may move.

36 Exercise: Fixed atoms and rotatable bonds Drag If two atoms in a rotatable bond are selected -Left Drag will rotate about the bond. If no atoms are fixed, the small group rotates by default. The larger group can be forced to rotate by fixing an atom in the smaller group Drag FIX this atom

37 Meters and Measurement 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. (Edit | Measure) or (RHS | Measure…)

38 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.

39 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.

40 MOE Selection Menu Invert current selection Atom Selection Tool for advanced selecting Save and Restore selection sets Pull down menus for selection by property, element, extension or other criteria Deselect all atoms Knowledge-based selectors for different parts of protein/ligand bound structures Extend selection set Selection state of residues is coordinated with the Sequence Editor

41 The Atom Selector Other Selection Options: 1.Accessibility 2.Chirality 3.Connectivity 4.Geometry 5.General 6.Pharmacophore 7.Protein (e.g. alpha carbon) Logic Operations Select by elements and atom types Extend Selection Criteria Save and Load selection sets; create named sets Selection Restrictions Select by name Select by SMILES string substructure General Selection actions MOE | Selection | Atom Selector

42 Moving Atoms with the Middle Mouse Button Middle click to center on atom Middle Drag: XY Translate XY Rotate Middle Drag: Zoom in/out center of rotation Middle Drag: XY Rotate selected only - Middle Drag: XY Translate selected only

43 Exercise: Moving Atoms with the Middle Mouse Button 1.View the coordinate system (Render | Draw | Coordinate Axes). 2.Rotate view about the XY axes (Middle Drag). 3.Translate view ( - Middle Drag). 4.Middle click on the carbonyl O to move the center of rotation. 5.Remove the coordinate axes by de-selecting (Render | Draw | Coordinate Axes) 6.Deselect all atoms (Left-click in space or (Selection | Clear)). 7.Move a selected subset with -Middle Drag (rotate) Middle Drag (translate).

44 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.

45 Exercise: Small Molecule Rendering Select and render as ‘Space Filling’ Select group and render as ‘Stick’ 1.Deselect all atoms. 2.Use Left drag click to select part of the molecule. Render it as space filling (Render | Space Filling). 3.Select other parts of the molecule using left-drag or other methods, and render them as stick, ball and stick, or line. Rendering actions apply to: All atoms (if none are selected) Selected atoms only (if there are selected atoms)

46 Protein Backbone Rendering MOE | Render | Backbone or MOE | Popup | Backbone Turn off backbone Various Backbone rendering styles Backbone coloring options

47 Exercise: Open PDB file prior to rendering complex 1.Close the current system: MOE | File | Close 2.Select the file MOE | File | Open $MOE/sample/mol/1pph.pdb. 3.Press ‘Load PDB File’. 4.A variety of options are available in the PDB File panel. Choose to centre the view and press ‘OK’.

48 Exercise: Rendering Trypsin with Ligand 5.Select the water molecules (Selection | Solvent) and delete them (RHS | Delete). 6.Select the ligand(s) (Selection | Ligand) and render as space filling (Render | Space Filling). 7.Use Render | Color to select a desired colour for the selected atoms (green). 8.Deselect the atoms 9.Draw a backbone ribbon through the selected atoms (Render | Backbone | Slab Ribbon). 10.Color the backbone by Chain Color (Render | Backbone | Color | Chain Color). 11.Hide the selected protein atoms (Render | Hide | Receptor). 12.Click on empty space to clear selection state.

49 Exercise: Protein-Ligand Pocket Rendering 1.Turn the backbone off (MOE|Popup|Backbone|None) 2.Show ligand and pocket (MOE|Popup|Show|Ligand, Pocket) 3.Label the residues (MOE | RHS | Label | Residue) 4.Draw H-bonds (Render | Draw | Hydrogen Bonds) 5.Center the image (RHS | View) which should now look like the image on the left. 6.Save the system as a MOE file, MOE | File | Save

50 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. v u r P Preference for Hydrophilic Contacts Preference for Hydrophobic Contacts

51 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

52 Exercise: Contact Statistics in Pocket 1.Open the Contact Statistics panel: MOE | Compute | Surfaces and Maps 2.Setup the panel as follows Surface: Contact Preference 3.Press Apply. 5. Save to a MOE file (File | Save) ‘’ toggling on Graphics: All in panel

53 Exercise: Receptor Molecular Surfaces 1.Close the current system. (File | Close). 2.Disable hydrogen bond selection by de-selecting MOE | Render | Draw | H bonds 3.Open the files (MOE | File | Open ) $MOE/sample/mol/ $MOE/sample/mol/ 4.Calculate partial charge (MOE | Compute | Partial Charge) and enable “Adjust Hydrogens and Lone Pairs as Required” 5.Draw a electrostatic surface about the pocket (MOE|Compute|Surfaces and Maps) 6.Name the surface ‘Pocket Surface’ 7.Color by Electrostatics 8.Press Apply

54 Exercise: Receptor Molecular Surfaces 1.To isolate the pocket atoms, press Isolate on the panel 2.Turn off backbone (MOE|Popup|Backbone|None) 3.Select the pocket atoms (MOE|Popup|Select|Pocket) 4.Label the residues with the residue name (MOE|RHS|Label|Residue)

55 Exercise: Ligand Molecular Surfaces 1.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 2.Press Apply

56 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

57 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

58 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

59 Exercise: 2D Protein-Ligand Interactions 1.Hide all surfaces (MOE | Window | Graphic Object). Select and Hide each surface 2.Open MOE | Compute | Ligand Interactions

60 Exercise: Protein-Ligand Interactions substitution contour amount of ligand contact solvent exposure greasy residue acidic residue polar residue backbone donor/acceptor sidechain donor

61 Exercise: Protein-Ligand Interactions In the main MOE window, observe the relative strength of the ideal hydrogen geometry, shown as dotted lines 1.In the Ligand Interactions panel, select 3D Contact Style 2.Turn ON Residue H-bond Distance. Residue hydrogen bonds are scored and distance metrics are drawn in the main MOE window

62 2. The Sequence Editor MOE Window - 3D molecular data is displayed in the Sequence Editor as 2D data: bound ligand(s) protein chain(s) water chain(s) The SE Displays a ‘2D’ view of the molecular data 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 Open SE… (MOE | SEQ) or -Q

63 Anatomy of the Sequence Editor (SE) Chain Label Chain Number Residues Alignment Ruler Secondary Structure Bars Red = helices Yellow = sheets Blue/Green = H-bonded Turns Footer SE Menu

64 SE Menu Command Conventions Commands from the Sequence Editor are preceded by SE. (SE | Selection | Residue Selector) Synchronize selection of objects in MOE Window or DBV (via MOE or SE | Selection | Synchronize)

65 Data Hierarchy in MOE

66 Exercise: Molecular Hierarchy 1.For the loaded biotin-streptavidin system, toggle off the molecular surfaces, at MOE | Windows | Graphic Objects. Select the surface and press Hide. 2.Show receptor, using MOE | Render | Show | Receptor. 3.Clear Labels (MOE | RHS | Label | Clear) 4.Open the Sequence Editor (MOE | SEQ). The system should appear as shown: 4. Click in empty space to clear selection state

67 Exercise: Molecular Hierarchy (cont.) 5.Color the atoms by chain color (MOE | Render | Color | Chain) 6.Turn on the compound names (SE | Display | Compound Name) 7.Turn on the secondary structure color bars (SE | Display | Actual Secondary Structure).

68 Selecting Objects in the Sequence Editor Left Drag: Selection Box Chain Selection: Click: Chains one at a time Multiple Chains a range of chains Select residues one at a time Select Multiple Residues Select range of residues

69 Sequence Editor Popup Menus Open the SE Popup menus by right-clicking over the areas shown below:

70 Exercise: Using SE for Protein Rendering 1.Select protein chain (chain 2). Position mouse over chain and use Right mouse button to get Chain popup. 2.Select Backbone | Slab Ribbon, and 3.Backbone |Color | Chain color 4.Hide receptor (Atoms | Hide) 5.Select Chain 1 (ligand) and use popup menu to Render | Space Filling

71 Exercise: Using SE for Protein Rendering (cont.) 6.Close the current system (MOE | RHS | Close) 7.Close all windows except the main MOE window

72 3. The MOE Database Viewer Character, numeric and molecular data fields Molecular Data easily transferred between database and MOE Window Full 3D molecular structure

73 Anatomy of the Database Viewer (DBV) DBV CLI Entry Numbers Field Headers Data Cells Menu Bar

74 DBV Menu Command Conventions Commands from the Database Viewer preceded by DBV (DBV | Entry | Show All Entries)

75 DBV Left Mouse Button Commands Select entries/fields one at a time Select multiple entries/fields Select range of entries/fields

76 DBV Popup Menus The Popup Menus are invoked with the right mouse button

77 Exercise: Opening a MOE Database Viewer 1.(File | Open) Select the file $MOE/sample/mol/opiates_analog.mdb. 2.Open in a database viewer (Open in Database Viewer).

78 Exercise: Opening a MOE Database Viewer (cont.) XY Rotate Middle Drag: Zoom in/out 3.Left-Diagonal drag on a molecule cell to enlarge it. 4.Middle-drag in the molecule cell to rotate the view. Enlarge Molecule View: Left Diagonal Drag on Molecule Cell Middle Drag:

79 Exercise: Database Printing and Tiling 1.(DBV | File | Print) 2.Click on ‘Tile Molecule Field’. 3.Select ‘Display Entry Number’ and choose the footer to be the field ‘name’. 4. Change Grid: 3x4

80 Exercise: Copying Morphine from the DBV 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) 1.Close the current system in the MOE Window.

81 Exercise: Protonate the nitrogen atom in morphine 1.Left-click on the nitrogen atom, so that it becomes highlighted. 2.Left-click on the ‘Builder’ button on the RHS of the menu bar. 3.Select +1 for the ionisation state. 4.The nitrogen atom is then protonated.

82 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. Molecular Mechanics

83 Potential Energy in MOE Toggle on/off terms in the potential Partial charge calculation according to selected potential E = E STR + E ANG + E STB + E TOR + E OOP + E ELE + E VDW + E SOL Load different forcefields Forcefield parameter file Forcefield title No. of parallel processor threads to be used Adjust electrostatics implementation Adjust non-bonded interaction switching function

84 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

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

86 System energy components 2. Choose MOE | Compute | Potential Energy Exercise: Forcefield Energy Minimizations (2) Potential energy components are also shown in the SVL window

87 Tether Weight (kcal/mol A 2 ) Automatically assign partial charges Automatically add H’s (and LPs if required) Force current (R/S) stereochemistry Minimizations may be forcefield, or semi-empirical (MOPAC 7) Hamiltonian based Potential Setup window Exercise: Forcefield Energy Minimizations (3)

88 Minimized Morphine Exercise: Forcefield Energy Minimizations (4) 3. Use the defaults in the panel and press OK To minimize the molecule, select (MOE | Compute | Energy Minimize)

89 PM3, AM1 or MNDO Option to plot and view orbitals (HOMO and LUMO) Exercise: MOPAC Minimization Select (MOE | Compute | Energy Minimize) To view HOMO/LUMO orbitals go to (MOE | Window | Graphic Objects)

90 1.Close the current system (RHS | Close) 2.Open biotin and its receptor (MOE | File | Open ‘$MOE/sample/mol/ and’ 3.Add Hydrogen atoms and compute partial charges (MOE | Compute | Partial charge) 4.Select the ligand. Right click in the main MOE window to get popup panel. Popup | Select | Ligand 5.Choose MOE | Compute | Potential Energy Calculating Interaction Potential Energies ALL: total system E INT: selected – unselected interaction E SEL: selected only E

91 Exercise: Dihedral Energy Plots 1.Close current system. Open $MOE/sample/mol/ 2.Add hydrogen atoms (MOE | Edit | Hydrogens | Add Hydrogens) 3.Open the dihedral energy plot panel: MOE | Compute | Mechanics | Dihedral Energy Plot. 4.Select four consecutive carbon atoms in a dihedral. Plots the energy about a single rotatable bond.

92 Exercise: Dihedral Contours 1.Open the Dihedral Contour prompt (MOE | Compute | Mechanics | Dihedral Contour Plot). 2.Select four consecutive carbon atoms in one dihedral, followed by four consecutive carbon atoms in another dihedral. Plots the energy contours about two rotatable bond.

93 Forcefield Restraints: Energy terms E RESTRAINT =  E D istance +  E Angle +  E Torsion The 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. E D istance E Angle E Torsion

94 Creating Forcefield Restraints E Distance E Angle E Torsion = ( max (0, L 2 - r 2 ) 3 + max (0, r 2 - U 2 ) 3 ) * w = (max(0, cos a - cos L) 3 + max(0, cos U - cos a) 3 ) * 100 w = ( (1 - cos max(0,d - L)) 3 + (1 - cos max(0,U - d)) 3 * 10000w 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.

95 Exercise: Creating Forcefield Restraints 1.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. 2.Similarly, create an angle restraint (L = 115 0, U = 135 0, w = 1) between the carboxylate C and the O and H atoms shown here. 3. Minimize the structure (Compute | Energy Minimize). Minimized with restraints

96 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 List of current restraints Edit selected restraint. Press ‘Apply’ to institute changes. Delete selected restraints

97 Exercise: Removing Restraints 1.Open the Tethers and Restraints panel (Window | Potential Setup | Restraints). 2.Delete all the current distance and angle restraints. 3.Re-minimize the molecule (Compute | Energy Minimize). Minimized without restraints Minimized with restraints

98 Exercise: Using the GizMOE Minimizer 1. With biotin in the system, start the GizMOE Minimizer. MOE | GizMOE | Minimizer 2. Left drag to select and move part of the molecule. Then watch how the energy and geometry are automatically updated. The GizMOE Minimizer is a minimizer that runs continuously in the background. 3.Turn off the GizMOE Minimizer. Click the Cancel button and choose GizMOE_Minimizer[]. If necessary re-minimize the system (RHS | Minimize) Drag Translate Selected Atoms Only

99 Conformational Searching Systematic Conformational Search Stochastic Conformational Search Conformational Database Import Molecular Dynamics Conformational search methods available in MOE Generation of different conformations of a molecule or a complex is very useful for drug design.

100 Stochastic Conformational Search Torsion Space E Energy Cutoff E0E0 1. Perturb geometry 2. Minimize Random sampling of local minima on the potential energy surface

101 Stochastic Conformational Search Panel Output database Randomly: Invert chiral centers Rotate torsions Perturb xyz coordinates Conformation Generation: Conformation Minimization:

102 Systematic Conformational Search Exhaustive incremental dihedral rotation search Torsion Space E Cutoff E0E0

103 Systematic Conformational Search Panel Set dihedral increment Add/Remove dihedrals from list Output Database Minimise structures List of bonds to undergo rotation

104 Exercise: Systematic Conformational Searching (1) 1.Close the current system (RHS | Close) 2.Open up the MOE file for the molecule built earlier (MOE | File | Open ‘’). 3.Perform a systematic search on this molecule using the default options (MOE | Compute | Conformations | Systematic Search) 4.Left-Drag in DBV molecule cell to view structures. Enlarge Molecule View: Left Diagonal Drag on Molecule Cell

105 1.Open (DBV | Compute | Descriptors). 2.Enter ‘ Energy’ in the Filter field. 3.Select the descriptor (Left mouse click once) “ E Potential Energy” and press OK. Exercise: Systematic Conformational Searching (2)

106 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.

107 Superposing Conformations Mol field to perform calculations on Database to perform calculations on Measurements to perform on database Superposition of conformers in database Auto-Label atoms by element and number

108 Exercise: Superposing Conformations 1.Left mouse drag to select the methyl substituted pyridine ring 2.Bring up the Conformation Geometries panel. (DBV | Compute | Conformation Geometry…) 3.Change Molecule Field: to Overwrite Current Field. 4.Click on the Selected Atoms buttons. 5.Click on the Superpose button.

109 Exercise: Superposing Conformations (cont.) 6.Shift Left mouse click over a subset of entries (try entries 1 to 5) 7.Use Molecule Cell popup to Copy Selected Entries to MOE Window 8.Observed the superposed conformations 9.Color by chain using (MOE | Popup | Color | Chain)

110 Diverse Conformational Subset 1.Open the Diverse Subset panel (DBV | Compute | Diverse Subset). 2.Set the Output Limit to Choose ‘Conformation’ as the selection method. 4.Press OK to start calculation.

111 Exercise: Diverse Conformers Subsets 6.Copy 20 diverse conformers to MOE with popup. Shift Left click over entries 1 to Position mouse in mol field and use Right mouse button to get Popup. Select Copy Selected to MOE 8.Remember to select Clear Molecular Data 9.Render conformers as stick (MOE | Render | Stick) 5.Use Field popup to Sort Up on $DIVPRIO.

112 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.

113 Exercise: Interactive Superpose (1) 1.Close the current system and open (File | Open) $MOE/sample/mol/ b 2.Select entry 1 and 7 (morphine and heroin). Copy to MOE window 3.If molecules are superposed, separate by Ctl- Left click on an atom of one molecule, to select entire molecule. 4.Separate by moving selected molecule using Shift-Alt-Middle mouse 5.Center the view (RHS | View). 6.Render the structures as ball and stick (Render | Ball and Stick). 7.Hide the hydrogens (Render | Hide | Hydrogens). 8.Initiate superpose (Edit | Superpose)

114 Exercise: Interactive Superpose (2) 6.For Set 1 select the indicated oxygens labelled (1) on each molecule 7.Press Set: 2 in the CLI prompt and select the indicated aromatic ring carbons labelled (2) 8.Press Set: 3 in the CLI prompt and select the indicated oxygen atoms directly connected to the benzenes labelled (3) 9.With the minimum 3 point sets specified, the Superpose is possible. Press Superpose to superpose the structures. 10.Pressing Superpose will superpose the structures based on an optimal RMSD.

115 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

116 Exercise: Flexible Alignment of Opiates (1) 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 2.Ensure that the partial charges have been set, using MOE | Compute | Partial Charges. 3.Select one of the molecules using Ctl-Left mouse click on an atom of one molecule and fix it: MOE | Edit | Potential | Fix.

117 6. Choose MOE | Compute | Conformations| Flexible Alignment. Decrease the iteration limit down to 20, instead of 200. Similarity terms and weighting 7. Preserve defaults and press OK Exercise: Flexible Alignment of Opiates (2)

118 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! Exercise: Flexible Alignment of Opiates (3)

119 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. Exercise: Flexible Alignment of Opiates (4)

120 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

121 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).

122 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.

123 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

124 Exercise: Opening a MOE Database Viewer 1.(File | Open) Select the file $MOE/sample/mol/blood_brain.mdb. 2.Open in a database viewer (Open in Database Viewer). 3.Save a local copy (DBV | File | Save ‘ bbb.mdb’ )

125 Exercise: Calculating Descriptors 1. Open the QuaSAR-Descriptor panel (DBV | Compute | Descriptors). Descriptor Filter 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

126 Exercise: Sort by Activity 1. Open the Sort Database panel (DBV | Compute | Sort). 2. Select Field: “logBB” 3. Enable “Descending” 4. Press OK Sort in descending order of logBB

127 Exercise: Plotting Data 1.Open the DBV Plot window (DBV | Display | Plot). 2.Select logBB as the numeric value to plot. 3.Use the Right button in the plot area to compute the range with the DBV Plot popup.

128 Mouse Actions in the DBV Plot Window Drag: Selection Box Left Click: Select points individually Drag on axis: Selection Range XY Translate Plot Drag: Zoom in/out of Plot Entry Selection is reflected in the DBV and the DBV Plot window

129 Exercise: Select actives 2.Notice selected entries are updated automatically in the database viewer 1.Select active compounds by using Left mouse drag in Plot:Display for all entries where logBB > 0. Select compounds with logBB > 0

130 Exercise: Hide Inactives 1.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 Hide all compounds with logBB < 0

131 Exercise: Look at active compounds 1.Launch database browser by going to (DBV | File | Browser) 3.Use forward/backward triangles to navigate 2.Select Subject:mol (2D) for depicted mode

132 Exercise: Plot descriptor and activity relationship 1.Show all entries (DBV | Entry | Show All Entries). 2.Start the database correlation plot prompt (DBV | Compute | Analysis | Correlation Plot…). 3.Pick ‘TPSA’ and ‘logBB’ to plot along X and Y.

133 Exercise: Show relationship between all fields 1.Start the database correlation matrix prompt (DBV | Compute | Analysis | Correlation Matrix…). 2.Press on TPSA/logBB to get same correlation plot

134 Exercise: Select actives Entry Selection is reflected in both the DBV and Correlation Plot Drag: Selection Box Use the Attributes menu to change look of the plot Select points in the plot:

135 Exercise: Show relationship of actives with logP(o/w) 1.Hide inactives, go to (DBV | Entry | Hide Unselected entries) 2.Start the database correlation plot prompt (DBV | Compute | Analysis | Correlation Matrix…). 3.Press on logP(o/w) / logBB to get correlation plot

136 Exercise: Show clustering of actives and inactives 1.Show all entries (DBV | Entry | Show All Entries) 2.Open 3D Plot (DBV | Compute | Analysis | 3D Plot) 3.Set X to “Weight”, Y to “TPSA”, Z to “logP(o/w)” 4.Set activity to “logBB” 5.Set Threshold to 0 6.Press Plot 7.Enlarge points using (MOE | Render | Ball and Line)

137 Pharmacophore Overview Aim: to find chemically unrelated molecules which share molecular features 3.Take conformations of a set of diverse molecules. 4.Annotate with PH4 features 5.Find hits which match the query. 1.Take an active molecule. 2.Annotate possible PH4 features 3.Create a query with these features HB Acceptor Aromatic

138 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. Activity threshold: binary or no activity Selection of Ph4 schemes that can be stored and loaded Specification of conformational method Modification of features / rules Output database Ligand database Pharmacophore search parameters Feature list and feature properties Parameters for structure alignment Text report

139 Exercise: Pharmacophore Elucidation I 1.Open Elucidator panel in (MOE | Compute | Conformations | Pharmacophore Elucidator) 2.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 4.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) 5.Remain with the default Ph4 scheme (CHD) and click OK. 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):

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

141 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.

142 4. The SVL Commands Window 1.Open the SVL Commands Window with (RHS | SVL) SVL is a powerful language designed to allow you to customize MOE and extend MOE with your own functions

143 Exercise: SVL Commands Window 1.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’

144 Basic SVL windows in MOE Text Editor (TED) ASCII file / SVL program editor Crash History Source-level error trace-back Modules & Tasks Manager Program control / Source Code

145 Appendices

146 Forcefield File alkane.ff : Atom Typing Block #moe:forcefield #comment lines titleALKANE disableoop stb itortype CTC'sp3 C'type HCH'H attached to alphatic C'[rules] # TYPE ASSIGNMENT RULES CTmatch '[CX4]‘ HCmatch '[#1]C‘ …

147 Forcefield File alkane.ff : Bond Stretch Block [str] # BOND STRETCH #codeT1T2LENK2K3 K4bci # *CTCT *CTHC

148 Forcefield File alkane.ff : Angle Bend Block [ang] # ANGLE BEND ang-functionangle #CODET1T2T3ANG K2 K3 K4 # *CTCTCT *CTCTHC *HCCTHC

149 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

150 Forcefield File alkane.ff : Electrostatics Block [nonbonded] # nonbonded information ele-dielectric 1# dielectric+distance dependent flag ele-buffer 0# electrostatic buffering ele-scale14 1 # 1-4 interaction scaling ele-charge-fcnalkane# svl fcn to compute charges

151 Forcefield File alkane.ff : VDW Block vdw-scale141 [vdw] # VDW PARAMTERS ---- #T1T2REPSmn # CTCT CTHC HCHC

152 Visualization Setup: Coloring Set colors of objects Press Apply to institute changes Restore defaults Save new settings as defaults MOE | Render | Setup…

153 Visualization Setup: Dimensions Protein Ribbon dimensions Atom and Bond dimensions

154 Visualization Setup: Lighting and Projection

155 SVL and MOE-batch MOE/batch Terminal-style interface (no GUI). SVL commands entered at prompt. Used for scripting long tasks and automating procedures.

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