Abstract
Interfacial waters are considered to play a crucial role in protein–protein interactions, but in what sense and why are they important? Here, using molecular dynamics simulations and statistical thermodynamic analyses, we demonstrate distinctive dynamic characteristics of the interfacial water and investigate their implications for the binding thermodynamics. We identify the presence of extraordinarily slow (~1,000 times slower than in bulk water) hydrogen-bond rearrangements in interfacial water. We rationalize the slow rearrangements by introducing the “trapping” free energies, characterizing how strongly individual hydration waters are captured by the biomolecular surface, whose magnitude is then traced back to the number of water–protein hydrogen bonds and the strong electrostatic field produced at the binding interface. We also discuss the impact of the slow interfacial waters on the binding thermodynamics. We find that, as expected from their slow dynamics, the conventional approach to the water-mediated interaction, which assumes rapid equilibration of the waters’ degrees of freedom, is inadequate. We show instead that an explicit treatment of the extremely slow interfacial waters is critical. Our results shed new light on the role of water in protein–protein interactions, highlighting the need to consider its dynamics to improve our understanding of biomolecular bindings.
Highlights
In this connection, it has been suggested that water-mediated contacts substantially complement direct protein–protein contacts, providing an additional layer of biomolecular recognition[15, 16]
Recent computational studies have reported on the relevance of explicitly handling “key” interfacial waters in protein–protein interaction[18] and protein–ligand binding[19]: for example, including two, rather than all, interfacial water molecules was crucial to correctly obtaining the trends observed in mutation effects on protein–protein binding affinity[18]; in another study, explicitly taking into account interfacial water molecules ranging in number (Nwat) from 30 to 70 significantly improved the correlation with the experimental binding affinities for four different systems, where the optimum value of Nwat depended on the specific system[19]
We find that the conventional approach to the water-mediated interaction, which assumes the time-scale separation between the protein and hydration water dynamics, fails owing to the extremely slow dynamics exhibited by the interfacial waters
Summary
It has been suggested that water-mediated contacts substantially complement direct protein–protein contacts, providing an additional layer of biomolecular recognition[15, 16]. We investigate the dynamic and thermodynamic features of interfacial water in the barnase– barstar complex[15]. This is a well-studied paradigm for protein–protein interactions and is an ideal system for analyzing the interfacial water because X-ray measurements indicate the presence of waters filling the gap between the binding surfaces[15, 20]. Thereby, we would like to shed new light on the role of water in protein–protein interactions based on a dynamic view point
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