Transcript 1.Jeremy_Introduction_of_Protein_Simulation_and_Drug_Design

Introduction to Protein
Simulations and Drug Design
Jeremy C. Smith, University of Heidelberg
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Computational
Molecular Biophysics
The Boss
Universität
Heidelberg
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.
Computer Simulation - Basic Principles
Model System
or QM/MM
Potential
Molecular
Mechanical
Quantum
Mechanical
Molecular Mechanics Potential
V
 k b  b 
2
b
0
bonds


 k    
2
0

angles
N
  K 1  cosn      K    
2
n
0
dihedrals n 1
impropers
  
  
qq 
  4 ij  ij    ij      i j 






 rij 
i, j
 rij   i , j  Drij 

12
6
Simulation exploring the energy landscape
Some Simulation Methods
Normal Mode Analysis
(Jianpeng Ma)
Molecular Dynamics
(Bert de Groot/Phil Biggin)
Minimum-Energy Pathways
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
ANDREEA GRUIA
Protein
Folding
Exploring the
Folding
Landscape
7
Free energy (kcal/mol)
6
5
4
3
2
1
0
-1
(Johan Åqvist
3
4
Free Energy Calculations)
5
6
7
Distance CZ-CD (Å)
8
9
Safety in Numbers
BINDING
Substrate
Ligand
Protein
REACTION
STRUCTURAL
CHANGE
FUNCTION
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
Product
Reactant
Molecular
Mechanical
Quantum
Mechanical
SONJA SCHWARZL
ATP Hydrolysis by Myosin
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 (H2O)
(Bert de Groot)
ANDREEA GRUIA
Halorhodopsin - Chloride Pumping at Atomic Resolution
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.
Experiment
(Wilfred van Gunsteren)
Molecular Dynamics Simulation
Simplified Description
The Protein
Glass Transition
Onset of
Protein
Function
n
n
d
d
ALEX TOURNIER
Mode Incipient at Myoglobin Glass Transition
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
Drug Design
High Throughput
Screening
104 ligands per day
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?
Ligands
Trypsin
Target
Ligand Binding.
Ligand
Protein
Complex
Two Approaches:
1) Binding Free Energy Calculations
2) Empirical Scoring Functions
FRAUKE MEYER
What is the binding free energy?
entropic
effects
protein
polar and
K bind
k1
[C ]


k 1 [ P ][ L]
non-polar
ligand
k1
k-1
ΔGbind   RT ln Kbind
interactions
with the solvent
polar and
non-polar
water
complex
protein-ligand
interactions
Electrostatics:
Thermodynamic Cycle
Gel (  80)
  80
+
 Gsolv (P)  Gsolv (L)
 4
Gsolv(C )
Gel (  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
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
Cancer Biotechnology.
Detection of Individual p53Autoantibodies in Human Sera
ANDREA VAIANA
MARKUS SAUER
JUERGEN WOLFRUM
ANDREAS SCHULTZ
R6G
ab initio structure
RHF 6-31G* basis set
Fluorescence Quenching of Dyes
by Trytophan
Quencher
N
N
O
OH
O
MR121
Dye
N
Fluorescently labeled
Peptide
?
Analysis
r
Strategy:
Quenched
Results:
Healthy
Person
Serum
Cancer
Patient
Serum
Fluorescent
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)