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Issue 13, 2015
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Evaluation of water displacement energetics in protein binding sites with grid cell theory

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Abstract

Excess free energies, enthalpies and entropies of water in protein binding sites were computed via classical simulations and Grid Cell Theory (GCT) analyses for three pairs of congeneric ligands in complex with the proteins scytalone dehydratase, p38α MAP kinase and EGFR kinase respectively. Comparative analysis is of interest since the binding modes for each ligand pair differ in the displacement of one binding site water molecule, but significant variations in relative binding affinities are observed. Protocols that vary in their use of restraints on protein and ligand atoms were compared to determine the influence of protein–ligand flexibility on computed water structure and energetics, and to assess protocols for routine analyses of protein–ligand complexes. The GCT-derived binding affinities correctly reproduce experimental trends, but the magnitude of the predicted changes in binding affinities is exaggerated with respect to results from a previous Monte Carlo Free Energy Perturbation study. Breakdown of the GCT water free energies into enthalpic and entropic components indicates that enthalpy changes dominate the observed variations in energetics. In EGFR kinase GCT analyses revealed that replacement of a pyrimidine by a cyanopyridine perturbs water energetics up three hydration shells away from the ligand.

Graphical abstract: Evaluation of water displacement energetics in protein binding sites with grid cell theory

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Publication details

The article was received on 01 Dec 2014, accepted on 08 Jan 2015 and first published on 12 Jan 2015


Article type: Paper
DOI: 10.1039/C4CP05572A
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Phys. Chem. Chem. Phys., 2015,17, 8416-8426
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    Evaluation of water displacement energetics in protein binding sites with grid cell theory

    G. Gerogiokas, M. W. Y. Southey, M. P. Mazanetz, A. Hefeitz, M. Bodkin, R. J. Law and J. Michel, Phys. Chem. Chem. Phys., 2015, 17, 8416
    DOI: 10.1039/C4CP05572A

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