title: A physical reference state unifies the structure-derived potential of mean force for protein folding and binding.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute Center for Single Molecule Biophysics, Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York 14214, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Hongyi
authors.initials: H
authors.lastname: Zhou
authors.forename: Yaoqi
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000936:Antigen-Antibody Complex / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D016208:Databases, Factual; D019281:Dimerization; D006860:Hydrogen Bonding; D020407:Internet; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013816:Thermodynamics
chemical_list: D000936:Antigen-Antibody Complex; D011506:Proteins