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

Osman N. Yogurtcu, S. Bora Erdemli, Ruth Nussinov, Metin Turkay, Ozlem Keskin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3475-3485
Number of pages11
JournalBiophysical Journal
Volume94
Issue number9
DOIs
StatePublished - 1 May 2008

Funding

FundersFunder number
TÜBİTAK104T504
National Institutes of HealthN01-CO-12400
National Cancer InstituteZ01BC010441

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