Side-chain conformational changes upon protein-protein association

TL;DR

This study systematically analyzes side-chain conformational changes during protein-protein binding, revealing differences based on side-chain length and amino acid type, and highlighting implications for protein docking strategies.

Contribution

It provides a large-scale, detailed analysis of side-chain conformational changes upon protein association, emphasizing the role of side-chain length and amino acid properties.

Findings

Long side chains often undergo large conformational transitions.

Shorter side chains typically exhibit local, non-transition changes.

Binding increases hydrophobic interface areas, especially nonpolar regions.

Abstract

Conformational changes upon protein-protein association are the key element of the binding mechanism. The study presents a systematic large-scale analysis of such conformational changes in the side chains. The results indicate that short and long side chains have different propensities for the conformational changes. Long side chains with three or more dihedral angles are often subject to large conformational transition. Shorter residues with one or two dihedral angles typically undergo local conformational changes not leading to a conformational transition. The relationship between the local readjustments and the equilibrium fluctuations of a side chain around its unbound conformation is suggested. Most of the side chains undergo larger changes in the dihedral angle most distant from the backbone. The amino acids with symmetric aromatic (Phe and Tyr) and charged (Asp and Glu) groups show the opposite trend where the near-backbone dihedral angles change the most. The frequencies of the core-to-surface interface transitions of six nonpolar residues and Tyr exceed the frequencies of the opposite, surface-to-core transitions. The binding increases both polar and nonpolar interface areas. However, the increase of the nonpolar area is larger for all considered classes of protein complexes. The results suggest that the protein association perturbs the unbound interfaces to increase the hydrophobic forces. The results facilitate better understanding of the conformational changes in proteins and suggest directions for efficient conformational sampling in docking protocols.