Complementarity of stability patches at the interfaces of protein complexes: Implication for the structural organization of energetic hot spots

Yosef Y. Kuttner, Stanislav Engel

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


A rational design of protein complexes with defined functionalities and of drugs aimed at disrupting protein–protein interactions requires fundamental understanding of the mechanisms underlying the formation of specific protein complexes. Efforts to develop efficient small-molecule or protein-based binders often exploit energetic hot spots on protein surfaces, namely, the interfacial residues that provide most of the binding free energy in the complex. The molecular basis underlying the unusually high energy contribution of the hot spots remains obscure, and its elucidation would facilitate the design of interface-targeted drugs. To study the nature of the energetic hot spots, we analyzed the backbone dynamic properties of contact surfaces in several protein complexes. We demonstrate that, in most complexes, the backbone dynamic landscapes of interacting surfaces form complementary “stability patches,” in which static areas from the opposing surfaces superimpose, and that these areas are predominantly located near the geometric center of the interface. We propose that a diminished enthalpy–entropy compensation effect augments the degree to which residues positioned within the complementary stability patches contribute to complex affinity, thereby giving rise to the energetic hot spots. These findings offer new insights into the nature of energetic hot spots and the role that backbone dynamics play in facilitating intermolecular recognition. Mapping the interfacial stability patches may provide guidance for protein engineering approaches aimed at improving the stability of protein complexes and could facilitate the design of ligands that target complex interfaces.

Original languageEnglish
Pages (from-to)229-236
Number of pages8
JournalProteins: Structure, Function and Bioinformatics
Issue number2
StatePublished - 1 Feb 2018


  • backbone dynamics
  • energetic hot-spots
  • protein–protein interaction
  • stability patches
  • steered molecular dynamics simulation

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology


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