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Journal of Chemical Physics / Volume 134 / Issue 5 / ARTICLES / Theoretical Methods and Algorithms

J. Chem. Phys. 134, 054114 (2011); http://dx.doi.org/10.1063/1.3519057 (13 pages)

A water-swap reaction coordinate for the calculation of absolute protein–ligand binding free energies

Christopher J. Woods1, Maturos Malaisree2, Supot Hannongbua2, and Adrian J. Mulholland1

1Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom
2Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand

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(Received 23 August 2010; accepted 3 November 2010; published online 3 February 2011)

The accurate prediction of absolute protein–ligand binding free energies is one of the grand challenge problems of computational science. Binding free energy measures the strength of binding between a ligand and a protein, and an algorithm that would allow its accurate prediction would be a powerful tool for rational drug design. Here we present the development of a new method that allows for the absolute binding free energy of a protein–ligand complex to be calculated from first principles, using a single simulation. Our method involves the use of a novel reaction coordinate that swaps a ligand bound to a protein with an equivalent volume of bulk water. This water-swap reaction coordinate is built using an identity constraint, which identifies a cluster of water molecules from bulk water that occupies the same volume as the ligand in the protein active site. A dual topology algorithm is then used to swap the ligand from the active site with the identified water cluster from bulk water. The free energy is then calculated using replica exchange thermodynamic integration. This returns the free energy change of simultaneously transferring the ligand to bulk water, as an equivalent volume of bulk water is transferred back to the protein active site. This, directly, is the absolute binding free energy. It should be noted that while this reaction coordinate models the binding process directly, an accurate force field and sufficient sampling are still required to allow for the binding free energy to be predicted correctly. In this paper we present the details and development of this method, and demonstrate how the potential of mean force along the water-swap coordinate can be improved by calibrating the soft-core Coulomb and Lennard-Jones parameters used for the dual topology calculation. The optimal parameters were applied to calculations of protein–ligand binding free energies of a neuraminidase inhibitor (oseltamivir), with these results compared to experiment. These results demonstrate that the water-swap coordinate provides a viable and potentially powerful new route for the prediction of protein–ligand binding free energies.

© 2011 American Institute of Physics

Article Outline

  1. INTRODUCTION AND BACKGROUND
  2. METHOD DESCRIPTION
  3. VALIDATION AND DEVELOPMENT
    1. Soft-core parameter investigation
    2. Soft-core parameter optimization
    3. Investigating the positioning of the identity points
    4. Investigating the portability of the soft-core parameters
  4. APPLICATION TO A PROTEIN SYSTEM
  5. FUTURE WORK
  6. CONCLUSIONS

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KEYWORDS and PACS

Keywords

binding energy, biochemistry, drugs, free energy, molecular biophysics, proteins

PACS

  • 87.15.R-

    Reactions and kinetics

  • 87.15.kp

    Protein-ligand interactions

  • 87.15.A-

    Theory, modeling, and computer simulation

ARTICLE DATA

Digital Object Identifier
http://dx.doi.org/10.1063/1.3519057

PUBLICATION DATA

ISSN

0021-9606 (print)  
1089-7690 (online)

Publisher

$abstract.society.value is a Member of CrossRef American Institute of Physics

For access to fully linked references, you need to log in.
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