On the ability of molecular dynamics simulation and continuum electrostatics to treat interfacial water molecules in protein-protein complexes

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.

Modeling and Simulation in Cancer Nanomedicine

“…The Water inside the pore moves very slowly unlike the outside water molecules which diverge very fast from the protein. The observation is also supported by other published work [35,36]. Simulation outcomes may help the researchers further progress in targeting ion channels for therapeutic use.…”

Dynamics of Hydration Water Plays a Key Role in Determining the Binding Thermodynamics of Protein Complexes

“…The trapping free energy introduced in the present work serves as a valuable quantity not only to characterize the formation of the binding interface from the water’s perspective, but also to discuss how and whether the hydration water is rearranging to go from the unbound protein to bound complex. While the barnase–barstar complex studied here is known to be a system in which the interfacial waters are particularly immobile 46 , we anticipate the emergence of the extremely slow water relaxations to be a generic feature of hydrophilic protein–protein interfaces because electrostatic complementarity of the binding surfaces has been observed in numerous protein complexes 47 , 48 .…”

The Inclusion of Water Molecules in Residue Interaction Networks Identifies Additional Central Residues

“…In Lensink et al ( 2014 ) and Copie et al ( 2016 ), it was shown that Arg98.B contacts Glu30.A and Asn34.A through a water-mediated contact and Asp33.A via a buried water molecule. Here, we see that while Glu30.A was the only central residue found in the centrality analysis performed on the “dry” RIN, Arg98.B and Asp33.A are found in addition to Glu30.A in the “wet” centrality analysis.…”

“…The more specific the positioning of individual water molecules becomes, the more relevant will be their role in the precise functioning of proteins and their complexes. The computational prediction of water positions has already been an important issue in protein-ligand interaction (Boobbyer et al, 1989 ; Schymkowitz et al, 2005 ; Huggins and Tidor, 2011 ; Wang et al, 2011 ; Ross et al, 2012 ; de Ruyck et al, 2016 ; Jeszenoi et al, 2016 ), but also the modeling of the hydrogen-bonded network around proteins in light of protein-protein interaction has seen an increased interest (Jiang et al, 2005 ; Bui et al, 2007 ; Copie et al, 2016 ). More recently, the accurate prediction of the hydrogen-bonded network in the interface region has been the topic of several CAPRI blind prediction trials (Lensink et al, 2014 , 2017 ).…”