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

ABSTRACT: The relevance of water molecules for the recognition and the interaction of biomolecules is widely appreciated. In this paper we address the role that water molecules associated to protein complexes play for the functional relevance of residues by considering their residue interaction networks (RINs). These are commonly defined on the basis of the amino acid composition of the proteins themselves, disregarding the solvation state of the protein. We determine properties of the RINs of two protein complexes, colicin E2/Im2 and barnase/barstar, with and without associated water molecules, using a previously developed methodology and its associated application RINspector. We find that the inclusion of water molecules in RINs leads to an increase in the number of central residues which adds a novel mechanism to the relevance of water molecules for protein function.

SUBMITTER: Brysbaert G

PROVIDER: S-EPMC6193073 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Brysbaert Guillaume G Blossey Ralf R Lensink Marc F MF

Frontiers in molecular biosciences 20181011

The relevance of water molecules for the recognition and the interaction of biomolecules is widely appreciated. In this paper we address the role that water molecules associated to protein complexes play for the functional relevance of residues by considering their residue interaction networks (RINs). These are commonly defined on the basis of the amino acid composition of the proteins themselves, disregarding the solvation state of the protein. We determine properties of the RINs of two protein ...[more]

PMID: 30364190

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Project description:BackgroundHuman triosephosphate isomerase (HsTIM) deficiency is a genetic disease caused often by the pathogenic mutation E104D. This mutation, located at the side of an abnormally large cluster of water in the inter-subunit interface, reduces the thermostability of the enzyme. Why and how these water molecules are directly related to the excessive thermolability of the mutant have not been investigated in structural biology.ResultsThis work compares the structure of the E104D mutant with its wild type counterparts. It is found that the water topology in the dimer interface of HsTIM is atypical, having a "wet-core-dry-rim" distribution with 16 water molecules tightly packed in a small deep region surrounded by 22 residues including GLU104. These water molecules are co-conserved with their surrounding residues in non-archaeal TIMs (dimers) but not conserved across archaeal TIMs (tetramers), indicating their importance in preserving the overall quaternary structure. As the structural permutation induced by the mutation is not significant, we hypothesize that the excessive thermolability of the E104D mutant is attributed to the easy propagation of atoms' flexibility from the surface into the core via the large cluster of water. It is indeed found that the B factor increment in the wet region is higher than other regions, and, more importantly, the B factor increment in the wet region is maintained in the deeply buried core. Molecular dynamics simulations revealed that for the mutant structure at normal temperature, a clear increase of the root-mean-square deviation is observed for the wet region contacting with the large cluster of interfacial water. Such increase is not observed for other interfacial regions or the whole protein. This clearly suggests that, in the E104D mutant, the large water cluster is responsible for the subunit interface flexibility and overall thermolability, and it ultimately leads to the deficiency of this enzyme.ConclusionsOur study reveals that a large cluster of water buried in protein interfaces is fragile and high-maintenance, closely related to the structure, function and evolution of the whole protein.

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

Publications

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

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