RESTRICTED MOBILITY OF CONSERVED RESIDUES IN PROTEIN-PROTEIN INTERFACES IN MOLECULAR SIMULATIONS

¹ Johns Hopkins University
² Koc University
³ SAIC Frederick, Inc

^* To whom correspondence should be addressed. E-mail: okeskin{at}ku.edu.tr.

Submitted on June 12, 2007
Revised on July 26, 2007
Accepted on 7 November 2007

	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 prior to binding they are constrained in a bound-like configuration. To understand this behavior, we have analyzed the inter- and intra-chain 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 non-conserved. However, the monomer simulations reveal that conserved residues contribute dominantly to hydrogen bond formation prior to binding. Packing of conserved residues across the trajectories is significantly higher prior and following 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 pre-organized. Combined with previous studies, we conclude that conserved residues, hot spots, anchor and interface-buried residues may be similar residues, fulfilling similar roles.

Key Words: conserved residues, molecular dynamics, protein-protein interactions, protein-protein interfaces, residue hot spots