Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 33, Pages 13277-13282Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1312529110
Keywords
hydrophobicity; hydrodynamics; non-Markovian effects; dewetting transitions
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Funding
- National Institutes of Health [NIH-GM4330]
- National Science Foundation (NSF) [NSF-CHE-0910943]
- Computational Center for Nanotechnology Innovations at Rensselaer Polytechnic Institute
- NSF [OCI-1053575]
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [0910943] Funding Source: National Science Foundation
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A model of protein-ligand binding kinetics, in which slow solvent dynamics results from hydrophobic drying transitions, is investigated. Molecular dynamics simulations show that solvent in the receptor pocket can fluctuate between wet and dry states with lifetimes in each state that are long enough for the extraction of a separable potential of mean force and wet-to-dry transitions. We present a diffusive surface hopping model that is represented by a 2D Markovian master equation. One dimension is the standard reaction coordinate, the ligand-pocket separation, and the other is the solvent state in the region between ligand and binding pocket which specifies whether it is wet or dry. In our model, the ligand diffuses on a dynamic free-energy surface which undergoes kinetic transitions between the wet and dry states. The model yields good agreement with results from explicit solvent molecular dynamics simulation and an improved description of the kinetics of hydrophobic assembly. Furthermore, it is consistent with a non-Markovian Brownian theory for the ligand-pocket separation coordinate alone.
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