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

Universität Heidelberg Computational Molecular Biophysics The Boss

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

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

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

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

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

Safety in Numbers

Substrate Protein Ligand BINDING REACTION FUNCTION STRUCTURAL CHANGE

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 Quantum Mechanical Molecular Mechanical Reactant Product

ATP Hydrolysis by Myosin SONJA SCHWARZL

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 (H 2 O) (Bert de Groot)

Halorhodopsin - Chloride Pumping at Atomic Resolution ANDREEA GRUIA

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.

Molecular Dynamics Simulation Experiment Simplified Description (Wilfred van Gunsteren)

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

Mode Incipient at Myoglobin Glass Transition ALEX TOURNIER

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

High Throughput Screening  10 4 ligands per day  Drug Design But: Hit Rate 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

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

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

Electrostatics: Thermodynamic Cycle + +

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

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

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

RHF 6-31G* basis set R6G ab initio structure

MR121 Fluorescence Quenching of Dyes by Trytophan Dye Quencher

Fluorescently labeled Peptide ?

Analysis r

Strategy: QuenchedFluorescent Results: Healthy Person Serum Cancer Patient Serum

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)