Jeremy C. Smith, University of Heidelberg

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Introduction to Protein Simulations and Drug
Design
Jeremy C. Smith, University of Heidelberg
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Computational Molecular Biophysics
Universität Heidelberg
The Boss
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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.
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Computer Simulation - Basic Principles
Model System
or QM/MM Potential
Molecular Mechanics Potential
Simulation - exploring the energy landscape
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Some Simulation Methods
Normal Mode Analysis (Jianpeng Ma) Molecular
Dynamics (Bert de Groot/Phil Biggin) Minimum-Ener
gy Pathways
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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 FoldingFunnel
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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
ANDREEA GRUIA
Exploring the Folding Landscape
(Johan Åqvist Free Energy Calculations)
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Safety in Numbers
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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
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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 (H2O)
• (Bert de Groot)

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ANDREEA GRUIA
Halorhodopsin - Chloride Pumping at Atomic
Resolution
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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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Experiment
(Wilfred van Gunsteren)
Molecular Dynamics Simulation
Simplified Description
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The Protein Glass Transition
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ALEX TOURNIER
Mode Incipient at Myoglobin Glass Transition
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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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Drug Design
High Throughput Screening ?104 ligands per day
?
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
Target
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Ligand Binding.
Ligand
Protein
Complex
Two Approaches 1) Binding Free Energy
Calculations 2) Empirical Scoring Functions
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What is the binding free energy?
FRAUKE MEYER
entropic effects
protein
polar and non-polar interactions with the
solvent
ligand
k1
k-1
polar and non-polar protein-ligand interactions
water
complex
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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
SONJA SCHWARZL STEFAN FISCHER
Benzamidine-like Trypsin Inhibitors
Energy Terms and Results

- van der Waals proteinligand - hydrophobic
effect (surface area dependent) - electrostatic
interactions (continuum approach) -
translational, rotational, vibrational degrees of
freedom
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ANDREA VAIANA MARKUS SAUER JUERGEN
WOLFRUM ANDREAS SCHULTZ
Cancer Biotechnology.
Detection of Individual p53-Autoantibodies in
Human Sera
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R6G ab initio structure
RHF 6-31G basis set
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Fluorescence Quenching of Dyes by Trytophan
Quencher
MR121
Dye
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Fluorescently labeled Peptide
?
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Analysis
r
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Strategy
Quenched
Fluorescent
Results
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Things to learn (if you dont 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 elses
apparently very unrelated problem?
3) Where are the information sources?
4) Do not respect professors (question them)
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