A physical reference state unifies the structure-derived potential of mean force for protein folding and binding

Song Liu, Chi Zhang, Hongyi Zhou, Yaoqi Zhou

Research output: Contribution to journalArticlepeer-review

168 Scopus citations


Extracting knowledge-based statistical potential from known structures of proteins is proved to be a simple, effective method to obtain an approximate free-energy function. However, the different compositions of amino acid residues at the core, the surface, and the binding interface of proteins prohibited the establishment of a unified statistical potential for folding and binding despite the fact that the physical basis of the interaction (water-mediated interaction between amino acids) is the same. Recently, a physical state of ideal gas, rather than a statistically averaged state, has been used as the reference state for extracting the net interaction energy between amino acid residues of monomeric proteins. Here, we find that this monomer-based potential is more accurate than an existing all-atom knowledge-based potential trained with interfacial structures of dimers in distinguishing native complex structures from docking decoys (100% success rate vs. 52% in 21 dimer/trimer decoy sets). It is also more accurate than a recently developed semiphysical empirical free-energy functional enhanced by an orientation-dependent hydrogen-bonding potential in distinguishing native state from Rosetta docking decoys (94% success rate vs. 74% in 31 antibody-antigen and other complexes based on Z score). In addition, the monomer potential achieved a 93% success rate in distinguishing true dimeric interfaces from artificial crystal interfaces. More importantly, without additional parameters, the potential provides an accurate prediction of binding free energy of protein-peptide and protein-protein complexes (a correlation coefficient of 0. 87 and a root-mean-square deviation of 1.76 kcal/mol with 69 experimental data points). This work marks a significant step toward a unified knowledge-based potential that quantitatively captures the common physical principle underlying folding and binding. A Web server for academic users, established for the prediction of binding free energy and the energy evaluation of the protein-protein complexes, may be found at http://theory.med.buffalo. edu.

Original languageEnglish (US)
Pages (from-to)93-101
Number of pages9
JournalProteins: Structure, Function and Genetics
Issue number1
StatePublished - Jul 1 2004
Externally publishedYes


  • Binding stability
  • Docking decoys
  • Energy score functions
  • Knowledge-based potential
  • Potential of mean force
  • Reference state

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology


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