Jeremy C. Smith, University of Heidelberg

1. R P Introduction to Protein Simulations and Drug Design Jeremy C. Smith, University of Heidelberg

2. Computational Molecular Biophysics Universität Heidelberg The Boss

3. 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.

5. Molecular Mechanical Quantum Mechanical Computer Simulation - Basic Principles Model System or QM/MM Potential Molecular Mechanics Potential Simulation - exploring the energy landscape

6. Some Simulation Methods Normal Mode Analysis (Jianpeng Ma) Molecular Dynamics (Bert de Groot/Phil Biggin) Minimum-Energy Pathways

7. 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.

8. Protein FoldingFunnel

9. 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?….

10. Bundeshochleistungsrechner Hitachi SR8000-F1

11. ANDREEA GRUIA Protein Folding Exploring the Folding Landscape (Johan Åqvist Free Energy Calculations)

12. Safety in Numbers

14. BINDING Substrate Ligand Protein REACTION STRUCTURAL CHANGE FUNCTION

15. 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.

16. Product Molecular Mechanical Quantum Mechanical Reactant QM/MM - (Gerrit Groenhof/Ursula Rothlisberger) Model System

17. SONJA SCHWARZL ATP Hydrolysis by Myosin

18. 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.

19. 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)

20. ANDREEA GRUIA Halorhodopsin - Chloride Pumping at Atomic Resolution

22. 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.

23. Experiment (Wilfred van Gunsteren) Molecular Dynamics Simulation Simplified Description

24. Onset of Protein Function n n d d The Protein Glass Transition

25. ALEX TOURNIER Mode Incipient at Myoglobin Glass Transition

26. 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.

27. Power Stroke in Muscle Contraction.

28. 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

29. Drug Design High Throughput Screening 104 ligands per day  But: Hit Rate 10-6 per ligand

31. Drug Design Finding the Right Key for the Lock William Lipscomb: Drug design for Diabetes Type II

32. Is the structure of the target known?

33. Trypsin Ligands Target

34. Ligand Binding. Ligand Protein Complex Two Approaches: 1) Binding Free Energy Calculations 2) Empirical Scoring Functions

35. FRAUKE MEYER What is the binding free energy? entropic effects protein polar and non-polar interactions with the solvent ligand k1 k-1 polar and non-polar protein-ligand interactions water complex

36. Electrostatics: Thermodynamic Cycle + +

37. 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

38. 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

39. ANDREA VAIANA MARKUS SAUER JUERGEN WOLFRUM ANDREAS SCHULTZ Cancer Biotechnology. Detection of Individual p53-Autoantibodies in Human Sera

40. R6Gab initio structure RHF 6-31G* basis set

41. Fluorescence Quenching of Dyes by Trytophan Quencher MR121 Dye

42. Fluorescently labeled Peptide ?

43. Analysis r

45. Strategy: Healthy Person Serum Cancer Patient Serum Quenched Fluorescent Results:

46. 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)