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Restricted mobility of conserved residues in protein-protein interfaces in molecular simulations.

ABSTRACT: Conserved residues in protein-protein interfaces correlate with residue hot-spots. To obtain insight into their roles, we have studied their mobility. We have performed 39 explicit solvent simulations of 15 complexes and their monomers, with the interfaces varying in size, shape, and function. The dynamic behavior of conserved residues in unbound monomers illustrates significantly lower flexibility as compared to their environment, suggesting that already before binding they are constrained in a boundlike configuration. To understand this behavior, we have analyzed the inter- and intrachain hydrogen-bond residence-time in the interfaces. We find that conserved residues are not involved significantly in hydrogen bonds across the interface as compared to nonconserved. However, the monomer simulations reveal that conserved residues contribute dominantly to hydrogen-bond formation before binding. Packing of conserved residues across the trajectories is significantly higher before and after the binding, rationalizing their lower mobility. Backbone torsional angle distributions show that conserved residues assume restricted regions of space and the most visited conformations in the bound and unbound trajectories are similar, suggesting that conserved residues are preorganized. Combined with previous studies, we conclude that conserved residues, hot spots, anchor, and interface-buried residues may be similar residues, fulfilling similar roles.

SUBMITTER: Yogurtcu ON

PROVIDER: S-EPMC2292389 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Restricted mobility of conserved residues in protein-protein interfaces in molecular simulations.

Yogurtcu Osman N ON Erdemli S Bora SB Nussinov Ruth R Turkay Metin M Keskin Ozlem O

Biophysical journal 20080128 9

Conserved residues in protein-protein interfaces correlate with residue hot-spots. To obtain insight into their roles, we have studied their mobility. We have performed 39 explicit solvent simulations of 15 complexes and their monomers, with the interfaces varying in size, shape, and function. The dynamic behavior of conserved residues in unbound monomers illustrates significantly lower flexibility as compared to their environment, suggesting that already before binding they are constrained in a ...[more]

PMID: 18227135

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Project description:BACKGROUND:The maintenance of protein structural stability requires the cooperativity among spatially neighboring residues. Previous studies have shown that conserved residues tend to occur clustered together within enzyme active sites and protein-protein/DNA interfaces. It is possible that conserved residues form one or more local clusters in protein tertiary structures as it can facilitate the formation of functional motifs. In this work, we systematically investigate the spatial distributions of conserved residues as well as hot spot ones within protein-RNA interfaces. RESULTS:The analysis of 191 polypeptide chains from 160 complexes shows the polypeptides interacting with tRNAs evolve relatively rapidly. A statistical analysis of residues in different regions shows that the interface residues are often more conserved, while the most conserved ones are those occurring at protein interiors which maintain the stability of folded polypeptide chains. Additionally, we found that 77.8% of the interfaces have the conserved residues clustered within the entire interface regions. Appling the clustering characteristics to the identification of the real interface, there are 31.1% of cases where the real interfaces are ranked in top 10% of 1000 randomly generated surface patches. In the conserved clusters, the preferred residues are the hydrophobic (Leu, Ile, Met), aromatic (Tyr, Phe, Trp) and interestingly only one positively charged Arg residues. For the hot spot residues, 51.5% of them are situated in the conserved residue clusters, and they are largely consistent with the preferred residue types in the conserved clusters. CONCLUSIONS:The protein-RNA interface residues are often more conserved than non-interface surface ones. The conserved interface residues occur more spatially clustered relative to the entire interface residues. The high consistence of hot spot residue types and the preferred residue types in the conserved clusters has important implications for the experimental alanine scanning mutagenesis study. This work deepens the understanding of the residual organization at protein-RNA interface and is of potential applications in the identification of binding site and hot spot residues.

Dataset Information

Restricted mobility of conserved residues in protein-protein interfaces in molecular simulations.

Publications

Restricted mobility of conserved residues in protein-protein interfaces in molecular simulations.

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