Issue 13, 2015

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

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

Associated articles

Supplementary files

Article information

Article type
Paper
Submitted
01 dec 2014
Accepted
08 jan 2015
First published
12 jan 2015
This article is Open Access
Creative Commons BY license

Phys. Chem. Chem. Phys., 2015,17, 8416-8426

Author version available

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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