Side-Chain Conformational Preferences Govern Protein-Protein Interactions

Andrew M. Watkins, Richard Bonneau, Paramjit S. Arora

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Protein secondary structures serve as geometrically constrained scaffolds for the display of key interacting residues at protein interfaces. Given the critical role of secondary structures in protein folding and the dependence of folding propensities on backbone dihedrals, secondary structure is expected to influence the identity of residues that are important for complex formation. Counter to this expectation, we find that a narrow set of residues dominates the binding energy in protein-protein complexes independent of backbone conformation. This finding suggests that the binding epitope may instead be substantially influenced by the side-chain conformations adopted. We analyzed side-chain conformational preferences in residues that contribute significantly to binding. This analysis suggests that preferred rotamers contribute directly to specificity in protein complex formation and provides guidelines for peptidomimetic inhibitor design.

Original languageEnglish
Pages (from-to)10386-10389
Number of pages4
JournalJournal of the American Chemical Society
Issue number33
StatePublished - 24 Aug 2016
Externally publishedYes


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