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Jeremy C. Smith, University of Heidelberg Introduction to Protein Simulations and Drug Design R P
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Universität Heidelberg Computational Molecular Biophysics The Boss
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Protein Folding and Structure. Enzyme Reaction Mechanisms. Bioenergetic Systems e.g., ion transport, light-driven. Protein Dynamics and Relation to Function. Large-Scale Conformational Change. Ligand Binding and Macromolecular Association. Some Problems to be Solved
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Computer Simulation - Basic Principles Molecular Mechanics Potential Model System Quantum Mechanical Molecular Mechanical or QM/MM Potential Simulation - exploring the energy landscape
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Normal Mode Analysis (Jianpeng Ma) Molecular Dynamics (Bert de Groot/Phil Biggin) Minimum-Energy Pathways Some Simulation Methods
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Protein Folding and Structure. Enzyme Reaction Mechanisms. Bioenergetic Systems e.g., ion transport, light-driven. Protein Dynamics and Relation to Function. Large-Scale Conformational Change. Ligand Binding and Macromolecular Association.
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Protein Folding Funnel
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Protein Folding 1) What structure does a given sequence have? - comparative modelling - energy-based (´ab initio´)? - data-base based (´knowledge´)? 2) How does a protein fold? …..computer simulation?….
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Bundeshochleistungsrechner Hitachi SR8000-F1
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Protein Folding Exploring the Folding Landscape (Johan Åqvist Free Energy Calculations) ANDREEA GRUIA
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Safety in Numbers
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Substrate Protein Ligand BINDING REACTION FUNCTION STRUCTURAL CHANGE
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Protein Folding. Protein Structure. Enzyme Reaction Mechanisms. Bioenergetic Systems e.g.ion transport,light-driven. Protein Dynamics and Relation to Function. Large-Scale Conformational Change. Ligand Binding and Macromolecular Association.
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QM/MM - (Gerrit Groenhof/Ursula Rothlisberger) Model System Quantum Mechanical Molecular Mechanical Reactant Product
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ATP Hydrolysis by Myosin SONJA SCHWARZL
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Protein Folding. Protein Structure. Enzyme Reaction Mechanisms. Bioenergetic Systems e.g.ion transport,light-driven. Protein Dynamics and Relation to Function. Large-Scale Conformational Change. Ligand Binding and Macromolecular Association.
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Charge Transfer in Biological Systems Membranes and Membrane Proteins Light-Driven (Excited States)? (Gerrit Groenhof) Electron Transfer (Excited States?) Ion Transfer (H +,K +,Cl - ) Molecule Transfer (H 2 O) (Bert de Groot)
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Halorhodopsin - Chloride Pumping at Atomic Resolution ANDREEA GRUIA
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Protein Folding. Protein Structure. Enzyme Reaction Mechanisms. Bioenergetic Systems e.g.ion transport,light-driven. Protein Dynamics and Relation to Function. Large-Scale Conformational Change. Ligand Binding and Macromolecular Association.
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Molecular Dynamics Simulation Experiment Simplified Description (Wilfred van Gunsteren)
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The Protein Glass Transition d d n n Onset of Protein Function
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Mode Incipient at Myoglobin Glass Transition ALEX TOURNIER
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Protein Folding. Protein Structure. Self-Assembly of Biological Structures. Enzyme Reaction Mechanisms. Bioenergetic Systems e.g.ion transport,light-driven. Protein Dynamics and Relation to Function. Large-Scale Conformational Change. Ligand Binding and Macromolecular Association.
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Power Stroke in Muscle Contraction.
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Protein Folding. Protein Structure. Self-Assembly of Biological Structures. Enzyme Reaction Mechanisms. Bioenergetic Systems e.g.ion transport,light-driven. Protein Dynamics and Relation to Function. Large-Scale Conformational Change. Ligand Binding and Macromolecular Association. Drug Design
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High Throughput Screening 10 4 ligands per day Drug Design But: Hit Rate 10 -6 per ligand
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Drug Design Finding the Right Key for the Lock William Lipscomb: Drug design for Diabetes Type II
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Is the structure of the target known?
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Ligands Trypsin Target
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Protein Ligand Complex Ligand Binding. Two Approaches: 1) Binding Free Energy Calculations 2) Empirical Scoring Functions
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What is the binding free energy? ligand protein complex water polar and non-polar interactions with the solvent polar and non-polar protein-ligand interactions entropic effects k1k1 k -1 FRAUKE MEYER
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Electrostatics: Thermodynamic Cycle + +
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Methods flexibility (Jon Essex) MD (Daan van Aalten) scoring functions, virtual screening (Martin Stahl, Qi Chen) prediction of active sites (Gerhard Klebe) active site homologies
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Fast Calculation of Absolute Binding Free Energies: Interaction of Benzamidine Analogs with Trypsin Benzamidine-like Trypsin InhibitorsEnergy Terms and Results - van der Waals protein:ligand - hydrophobic effect (surface area dependent) - electrostatic interactions (continuum approach) - translational, rotational, vibrational degrees of freedom SONJA SCHWARZL STEFAN FISCHER
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Detection of Individual p53- Autoantibodies in Human Sera Cancer Biotechnology. ANDREA VAIANA MARKUS SAUER JUERGEN WOLFRUM ANDREAS SCHULTZ
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RHF 6-31G* basis set R6G ab initio structure
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MR121 Fluorescence Quenching of Dyes by Trytophan Dye Quencher
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Fluorescently labeled Peptide ?
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Analysis r
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Strategy: QuenchedFluorescent Results: Healthy Person Serum Cancer Patient Serum
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Things to learn (if you don´t know them already) 1) Which different angles can my problem be approached from? (talk to people from different fields). 2) Can I bring a new angle to someone else´s apparently very unrelated problem? 3) Where are the information sources? 4) ´Do not respect professors´ (question them)
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