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  • Title: A molecular dynamics approach to study the importance of solvent in protein interactions.
    Author: Samsonov S, Teyra J, Pisabarro MT.
    Journal: Proteins; 2008 Nov 01; 73(2):515-25. PubMed ID: 18452208.
    Abstract:
    Water constitutes the cellular environment for biomolecules to interact. Solvent is important for protein folding and stability, and it is also known to actively participate in many catalytic processes in the cell. However, solvent is often ignored in molecular recognition and not taken into account in protein-protein interaction studies and rational design. Previously we developed SCOWLP, a database and its web application (http://www.scowlp.org), to perform studies on the contribution of solvent to protein interface definition in all protein complexes of the PDB. We introduced the concept of wet spots, interfacial residues interacting only through one water molecule, which were shown to considerably enrich protein interface descriptions. Analysis of interfacial solvent in a nonredundant dataset of protein complexes suggested the importance of including interfacial water molecules in protein interaction studies. In this work we use a molecular dynamics approach to gain deeper insights into solvent contribution to protein interfaces. We characterize the dynamic and energetic properties of water-mediated protein interactions by comparing different interfacial interaction types (direct, dual and wet spot) at residue and solvent level. For this purpose, we perform an analysis of 17 representative complexes from two protein families of different interface nature. Energetically wet spots are quantitatively comparable to other residues in interfaces, and their mobility is shown to be lower than protein surface residues. The residence time of water molecules in wet spots sites is higher than of those on the surface of the protein. In terms of free energy, though wet-spots-forming water molecules are very heterogeneous, their contribution to the free energy of complex formation is considerable. We find that water molecules can play an important role in interaction conservation in protein interfaces by allowing sequence variability in the corresponding binding partner, and we discuss the important implications of our observations related to the use of the correlated mutations concept in protein interactions studies. The results obtained in this work help to deepen our understanding of the physico-chemical nature underlying protein-protein interactions and strengthen the idea of using the wet spots concept to qualitatively improve the accuracy of folding, docking and rational design algorithms.
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