Analysis of the impact of solvent on contacts prediction in proteins

Abstract

BackgroundThe correlated mutations concept is based on the assumption that interacting protein residues coevolve, so that a mutation in one of the interacting counterparts is compensated by a mutation in the other. Approaches based on this concept have been widely used for protein contacts prediction since the 90s. Previously, we have shown that water-mediated interactions play an important role in protein interfaces. We have observed that current "dry" correlated mutations approaches might not properly predict certain interactions in protein interfaces due to the fact that they are water-mediated.ResultsThe goal of this study has been to analyze the impact of including solvent into the concept of correlated mutations. For this purpose we use linear combinations of the predictions obtained by the application of two different similarity matrices: a standard "dry" similarity matrix (DRY) and a "wet" similarity matrix (WET) derived from all water-mediated protein interfacial interactions in the PDB. We analyze two datasets containing 50 domains and 10 domain pairs from PFAM and compare the results obtained by using a combination of both matrices. We find that for both intra- and interdomain contacts predictions the introduction of a combination of a "wet" and a "dry" similarity matrix improves the predictions in comparison to the "dry" one alone.ConclusionOur analysis, despite the complexity of its possible general applicability, opens up that the consideration of water may have an impact on the improvement of the contact predictions obtained by correlated mutations approaches.

Bound Water at Protein-Protein Interfaces: Partners, Roles and Hydrophobic Bubbles as a Conserved Motif

“…Using this principle, Samsonov et al . recently reported [25] that including solvent matrices in contact predictions [97] , [98] of protein-protein interfaces improve these predictions by 20-30%. However, no residue level information was reported.…”

“…Keskin and Nussinov [23] , [24] have described water inclusion as an alternative strategy for proteins to achieve optimum association. Pisabarro and colleagues have examined solvent at protein-protein interfaces [25] – [27] and have shown that considering water may improve protein contacts predictions [25] that are based on the principle of correlated mutations [28] - [31] . Several authors have discussed approaches for including water explicitly and implicitly in docking protocols, e.g., Jiang et al [32] , van Dijk and Bonvin [33] , Li and Lazaridis [34] , de Graaf et al [35] , Jackson, Gabb and Sternberg [36] , and Zuo, Gandhi and Mancera [37] .…”

Cre Recombinase and Other Tyrosine Recombinases

“…It has been well-established that interfacial water molecules have an important “linking” role by providing an extension to protein side-chains (i.e., they can occupy positions and play physicochemical roles analogous to amino acid functionalities) and establishing hydrogen-bonding networks. Furthermore, interfacial solvent has been shown to be more than simply space-filling or linking atoms but also key in assisting the conservation of protein interactions despite evolutive sequence …”

Docking glycosaminoglycans to proteins: analysis of solvent inclusion

“…In our previous work we performed statistical analysis of water-mediated interactions in protein interfaces based on the SCOWLP definition [32, 33] and characterized them from a dynamic and energetic point of view [34], showing indispensability of water-mediated interactions for a complete description of protein–protein interactions. The interacting solvent data obtained from SCOWLP also assisted to improve protein contact predictions [35]. We apply molecular dynamics (MD) approaches in order to further analyze the significance of water-mediated interactions in GAG-protein interfaces.…”