Calculation of Absolute Protein-Ligand Binding Free Energy from Computer Simulations

A general methodology for calculating the equilibrium binding constant of a flexible ligand to a protein receptor is formulated on the basis of potentials of mean force. The overall process is decomposed into several stages that can be computed separately: the free ligand in the bulk is first restra...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-05, Vol.102 (19), p.6825-6830
Main Authors: Woo, Hyung-June, Roux, Benoît, Berne, Bruce J.
Format: Article
Language:English
Subjects:
Binding Sites
Center of mass
Chemical Theory and Computation Special Feature
Computational Biology - methods
Computer Simulation
Crystallography, X-Ray
Electrostatics
Energy value
Free energy
Humans
Kinetics
Ligands
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - chemistry
Models, Molecular
Models, Statistical
Molecules
Peptides - chemistry
Phosphotyrosine - chemistry
Physical Sciences
Protein Binding
Protein Conformation
Receptors
Roux
Solvents
src Homology Domains
Thermodynamics
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Summary:A general methodology for calculating the equilibrium binding constant of a flexible ligand to a protein receptor is formulated on the basis of potentials of mean force. The overall process is decomposed into several stages that can be computed separately: the free ligand in the bulk is first restrained into the conformation it adopts in the bound state, position, and orientation by applying biasing potentials, then it is translated into the binding site, where it is released completely. The conformational restraining potential is based on the root-mean-square deviation of the peptide coordinates relative to its average conformation in the bound complex. Free energy contributions from each stage are calculated by means of free energy perturbation potential of mean force techniques by using appropriate order parameters. The present approach avoids the need to decouple the ligand from its surrounding (bulk solvent and receptor protein) as is traditionally performed in the double-decoupling scheme. It is believed that the present formulation will be particularly useful when the solvation free energy of the ligand is very large. As an application, the equilibrium binding constant of the phosphotyrosine peptide pYEEI to the Src homology 2 domain of human Lck has been calculated. The results are in good agreement with experimental values.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0409005102