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Jeremy C. Smith, University of Heidelberg

Introduction to Protein Simulations and Drug Design

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Universität Heidelberg

Computational Computational Molecular BiophysicsMolecular 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

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Model System

QuantumMechanical

MolecularMechanical

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 MethodsSome 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 FoldingFunnel

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

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0

1

2

3

4

5

6

7

Free

ene

rgy

(kca

l/mol

)

Distance CZ-CD (Å)(Johan ÅqvistFree 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

QuantumMechanical

MolecularMechanical

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

Membranesand Membrane Proteins

• Light-Driven (Excited States)? (Gerrit Groenhof)• Electron Transfer (Excited States?)• Ion Transfer (H+,K+,Cl-)• Molecule Transfer (H2O)

(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

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d

nn

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 DesignDrug Design

High Throughput Screening

104 ligands per day

Drug Design

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?

LigandsTrypsin

Target

Protein

Ligand

Complex

Ligand Binding.

Two Approaches:

1) Binding Free Energy Calculations 2) Empirical Scoring Functions

What is the binding free energy?

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1

1

LP

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k

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ligand

protein

complex

water

polar and

non-polar

interactions with the solvent

polar and

non-polar

protein-ligand interactions

entropic effects

k1 k-1

FRAUKE MEYER

Electrostatics: Thermodynamic Cycle

+

+

)(PGsolv )(LGsolv )(CGsolv

)80( elG

)4( elG

80

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

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

SONJA SCHWARZL

STEFAN FISCHER

Detection of Individual p53-Autoantibodies in Human Sera

Cancer Biotechnology.

ANDREA VAIANA MARKUS SAUER JUERGEN WOLFRUMANDREAS SCHULTZ

RHF 6-31G* basis set

R6G ab initio structure

O H

N

O

O

N

N

MR121

Fluorescence Quenching of Dyes by Trytophan

Dye

Quencher

Fluorescently labeled Peptide

?

Analysis

r

Strategy:

Quenched Fluorescent

Results:

HealthyPersonSerum

CancerPatientSerum

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)