Assessment of Hydration Thermodynamics at Protein Interfaces with Grid Cell Theory

Research output: Contribution to journalArticle

  • External authors:
  • Georgios Gerogiokas
  • Michelle W Y Southey
  • Michael P. Mazanetz
  • Alexander Heifetz
  • Michael Bodkin
  • Richard J. Law
  • J. Michel


Molecular dynamics simulations have been analyzed with the Grid Cell Theory (GCT) method to spatially resolve the binding enthalpies and entropies of water molecules at the interface of 17 structurally diverse proteins. Correlations between computed energetics and structural descriptors have been sought to facilitate the development of simple models of protein hydration. Little correlation was found between GCT-computed binding enthalpies and continuum electrostatics calculations. A simple count of contacts with functional groups in charged amino acids correlates well with enhanced water stabilization, but the stability of water near hydrophobic and polar residues depends markedly on its coordination environment. The positions of X-ray-resolved water molecules correlate with computed high-density hydration sites, but many unresolved waters are significantly stabilized at the protein surfaces. A defining characteristic of ligand-binding pockets compared to nonbinding pockets was a greater solvent-accessible volume, but average water thermodynamic properties were not distinctive from other interfacial regions. Interfacial water molecules are frequently stabilized by enthalpy and destabilized entropy with respect to bulk, but counter-examples occasionally occur. Overall detailed inspection of the local coordinating environment appears necessary to gauge the thermodynamic stability of water in protein structures.

Bibliographical metadata

Original languageEnglish
Pages (from-to)10442-10452
Number of pages11
JournalJournal of Physical Chemistry B
Issue number40
Early online date19 Sep 2016
StatePublished - 13 Oct 2016