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1 Department of Biochemistry and 2 Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA
(RECEIVED November 8, 2004; FINAL REVISION January 26, 2005; ACCEPTED January 26, 2005)
Success in high-resolution protein–protein docking requires accurate modeling of side-chain conformations at the interface. Most current methods either leave side chains fixed in the conformations observed in the unbound protein structures or allow the side chains to sample a set of discrete rotamer conformations. Here we describe a rapid and efficient method for sampling off-rotamer side-chain conformations by torsion space minimization during protein–protein docking starting from discrete rotamer libraries supplemented with side-chain conformations taken from the unbound structures, and show that the new method improves side-chain modeling and increases the energetic discrimination between good and bad models. Analysis of the distribution of side-chain interaction energies within and between the two protein partners shows that the new method leads to more native-like distributions of interaction energies and that the neglect of side-chain entropy produces a small but measurable increase in the number of residues whose interaction energy cannot compensate for the entropic cost of side-chain freezing at the interface. The power of the method is highlighted by a number of predictions of unprecedented accuracy in the recent CAPRI (Critical Assessment of PRedicted Interactions) blind test of protein–protein docking methods.
Keywords: protein–protein docking; side-chain modeling; rotamer minimization; side-chain entropy
Abbreviations: PDB, Protein Data Bank • RMSD, root-mean-square deviation.
Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041222905.
Reprint requests to: David Baker, Department of Biochemistry, Box 357350, University of Washington, Seattle, WA 98195, USA; e-mail: dabaker{at}u.washington.edu; fax: (206) 685-1792.
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