Computational Assessment of Protein–protein Binding Affinity by Reversely Engineering the Energetics in Protein Complexes

Bo Wang, Zhaoqian Su, Yinghao Wu

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The cellular functions of proteins are maintained by forming diverse complexes. The stability of these complexes is quantified by the measurement of binding affinity, and mutations that alter the binding affinity can cause various diseases such as cancer and diabetes. As a result, accurate estimation of the binding stability and the effects of mutations on changes of binding affinity is a crucial step to understanding the biological functions of proteins and their dysfunctional consequences. It has been hypothesized that the stability of a protein complex is dependent not only on the residues at its binding interface by pairwise interactions but also on all other remaining residues that do not appear at the binding interface. Here, we computationally reconstruct the binding affinity by decomposing it into the contributions of interfacial residues and other non-interfacial residues in a protein complex. We further assume that the contributions of both interfacial and non-interfacial residues to the binding affinity depend on their local structural environments such as solvent-accessible surfaces and secondary structural types. The weights of all corresponding parameters are optimized by Monte-Carlo simulations. After cross-validation against a large-scale dataset, we show that the model not only shows a strong correlation between the absolute values of the experimental and calculated binding affinities, but can also be an effective approach to predict the relative changes of binding affinity from mutations. Moreover, we have found that the optimized weights of many parameters can capture the first-principle chemical and physical features of molecular recognition, therefore reversely engineering the energetics of protein complexes. These results suggest that our method can serve as a useful addition to current computational approaches for predicting binding affinity and understanding the molecular mechanism of protein–protein interactions.

Original languageEnglish (US)
Pages (from-to)1012-1022
Number of pages11
JournalGenomics, Proteomics and Bioinformatics
Issue number6
StatePublished - Dec 2021


  • Binding affinity
  • Knowledge-based potential
  • Monte-Carlo simulation
  • Non-interfacial residue
  • Protein–protein interaction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Computational Mathematics


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