Optimizing energy functions for protein-protein interface design

Oz Sharabi, Chen Yanover, Ayelet Dekel, Julia M. Shifman

Research output: Contribution to journalArticlepeer-review


Protein design methods have been originally developed for the design of monomeric proteins. When applied to the more challenging task of protein-protein complex design, these methods yield suboptimal results. In particular, they often fail to recapitulate favorable hydrogen bonds and electrostatic interactions across the interface. In this work, we aim to improve the energy function of the protein design program ORBIT to better account for binding interactions between proteins. By using the advanced machine learning framework of conditional random fields, we optimize the relative importance of all the terms in the energy function, attempting to reproduce the native side-chain conformations in protein-protein interfaces. We evaluate the performance of several optimized energy functions, each describes the van der Waals interactions using a different potential. In comparison with the original energy function, our best energy function (a) incorporates a much "softer" repulsive van der Waals potential, suitable for the discrete rotameric representation of amino acid side chains; (b) does not penalize burial of polar atoms, reflecting the frequent occurrence of polar buried residues in protein-protein interfaces; and (c) significantly up-weights the electrostatic term, attesting to the high importance of these interactions for protein-protein complex formation. Using this energy function considerably improves side chain placement accuracy for interface residues in a large test set of protein-protein complexes. Moreover, the optimized energy function recovers the native sequences of protein-protein interface at a higher rate than the default function and performs substantially better in predicting changes in free energy of binding due to mutations.

Original languageAmerican English
Pages (from-to)23-32
Number of pages10
JournalJournal of Computational Chemistry
Issue number1
StatePublished - 15 Jan 2011


  • computational protein design
  • conditional random fields
  • energy functions
  • heterodimers
  • optimization
  • protein-protein interactions

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • Computational Mathematics


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