Jeremy C. Smith, University of Heidelberg Introduction to Protein Simulations and Drug Design R P.
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Transcript of Jeremy C. Smith, University of Heidelberg Introduction to Protein Simulations and Drug Design R P.
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Jeremy C. Smith, University of Heidelberg
Introduction to Protein Simulations and Drug Design
R
P
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
3 4 5 6 7 8 9-1
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
d
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
C
k
kKbind
bindbind KRTΔG ln
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)