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Introduction to Protein Simulations and Drug Design Jeremy C. Smith, University of Heidelberg R A E D G H B F C P Computational Molecular Biophysics The Boss Universität Heidelberg Some Problems to be Solved 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. Computer Simulation - Basic Principles Model System or QM/MM Potential Molecular Mechanical Quantum Mechanical Molecular Mechanics Potential V k b b 2 b 0 bonds k 2 0 angles N K 1 cosn K 2 n 0 dihedrals n 1 impropers qq 4 ij ij ij i j rij i, j rij i , j Drij 12 6 Simulation exploring the energy landscape Some Simulation Methods Normal Mode Analysis (Jianpeng Ma) Molecular Dynamics (Bert de Groot/Phil Biggin) Minimum-Energy Pathways 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. Protein Folding Funnel 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?…. Bundeshochleistungsrechner Hitachi SR8000-F1 ANDREEA GRUIA Protein Folding Exploring the Folding Landscape 7 Free energy (kcal/mol) 6 5 4 3 2 1 0 -1 (Johan Åqvist 3 4 Free Energy Calculations) 5 6 7 Distance CZ-CD (Å) 8 9 Safety in Numbers BINDING Substrate Ligand Protein REACTION STRUCTURAL CHANGE FUNCTION 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. QM/MM - (Gerrit Groenhof/Ursula Rothlisberger) Model System Product Reactant Molecular Mechanical Quantum Mechanical SONJA SCHWARZL ATP Hydrolysis by Myosin 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. 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 (H2O) (Bert de Groot) ANDREEA GRUIA Halorhodopsin - Chloride Pumping at Atomic Resolution 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. Experiment (Wilfred van Gunsteren) Molecular Dynamics Simulation Simplified Description The Protein Glass Transition Onset of Protein Function n n d d ALEX TOURNIER Mode Incipient at Myoglobin Glass Transition 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. Power Stroke in Muscle Contraction. 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 Drug Design High Throughput Screening 104 ligands per day But: Hit Rate 10-6 per ligand Drug Design Finding the Right Key for the Lock William Lipscomb: Drug design for Diabetes Type II Is the structure of the target known? Ligands Trypsin Target Ligand Binding. Ligand Protein Complex Two Approaches: 1) Binding Free Energy Calculations 2) Empirical Scoring Functions FRAUKE MEYER What is the binding free energy? entropic effects protein polar and K bind k1 [C ] k 1 [ P ][ L] non-polar ligand k1 k-1 ΔGbind RT ln Kbind interactions with the solvent polar and non-polar water complex protein-ligand interactions Electrostatics: Thermodynamic Cycle Gel ( 80) 80 + Gsolv(P) Gsolv (L) 4 Gsolv(C ) Gel ( 4) + 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 SONJA SCHWARZL STEFAN FISCHER Fast Calculation of Absolute Binding Free Energies: Interaction of Benzamidine Analogs with Trypsin Benzamidine-like Trypsin Inhibitors Energy Terms and Results - van der Waals protein:ligand - hydrophobic effect (surface area dependent) - electrostatic interactions (continuum approach) - translational, rotational, vibrational degrees of freedom Cancer Biotechnology. Detection of Individual p53Autoantibodies in Human Sera ANDREA VAIANA MARKUS SAUER JUERGEN WOLFRUM ANDREAS SCHULTZ R6G ab initio structure RHF 6-31G* basis set Fluorescence Quenching of Dyes by Trytophan Quencher N N O OH O MR121 Dye N Fluorescently labeled Peptide ? Analysis r Strategy: Quenched Results: Healthy Person Serum Cancer Patient Serum Fluorescent 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)