Abstract
Interfacial waters are increasingly appreciated as playing a key role in protein-protein interactions. We report on a study of the prediction of interfacial water positions by both Molecular Dynamics and explicit solvent-continuum electrostatics based on the Dipolar Poisson-Boltzmann Langevin (DPBL) model, for three test cases: (i) the barnase/barstar complex (ii) the complex between the DNase domain of colicin E2 and its cognate Im2 immunity protein and (iii) the highly unusual anti-freeze protein Maxi which contains a large number of waters in its interior. We characterize the waters at the interface and in the core of the Maxi protein by the statistics of correctly predicted positions with respect to crystallographic water positions in the PDB files as well as the dynamic measures of diffusion constants and position lifetimes. Our approach provides a methodology for the evaluation of predicted interfacial water positions through an investigation of water-mediated inter-chain contacts. While our results show satisfactory behaviour for molecular dynamics simulation, they also highlight the need for improvement of continuum methods.
Highlights
Consisting of two such regimes: a dynamical one, showing fast exchanges with bulk water that are unambiguously assisted by local protein motions, and a structural one that contributes to the structural integrity of the protein[9]
In terms of protein-water interaction, molecular dynamics (MD) has been used to study the microscopic dynamics of water around unfolded proteins[20] or to look at diffusion around intrinsically disordered proteins[21] but it allowed to establish the existence of coupled interactions between two distant proteins that were mediated by water[22]
In this work we have investigated the positions of interfacial water molecules from molecular dynamics simulations and an explicit-solvent continuum model
Summary
Consisting of two such regimes: a dynamical one, showing fast exchanges with bulk water that are unambiguously assisted by local protein motions, and a structural one that contributes to the structural integrity of the protein[9]. The prototypical example for strong electrostatic binding, the high-affinity barnase/barstar complex, features a large amount of water molecules in its protein-protein interface, a third of which are fully buried[15]. Interfacial water molecules are crucial to both stability and specificity of colicin DNase-immunity protein complexes[17]. On the other hand, have so far been mainly employed for a quantification of the energetics of protein interactions. Their common assumption relies on a constant permittivity of the solvent, both in the Generalized Born (GB) approach and the Poisson-Boltzmann (PB) theory. The latter relies on the partial differential equation for the electrostatic potential φ(r)
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