title: A "solvated rotamer" approach to modeling water-mediated hydrogen bonds at protein-protein interfaces.
abstract: Water-mediated hydrogen bonds play critical roles at protein-protein and protein-nucleic acid interfaces, and the interactions formed by discrete water molecules cannot be captured using continuum solvent models. We describe a simple model for the energetics of water-mediated hydrogen bonds, and show that, together with knowledge of the positions of buried water molecules observed in X-ray crystal structures, the model improves the prediction of free-energy changes upon mutation at protein-protein interfaces, and the recovery of native amino acid sequences in protein interface design calculations. We then describe a "solvated rotamer" approach to efficiently predict the positions of water molecules, at protein-protein interfaces and in monomeric proteins, that is compatible with widely used rotamer-based side-chain packing and protein design algorithms. Finally, we examine the extent to which the predicted water molecules can be used to improve prediction of amino acid identities and protein-protein interface stability, and discuss avenues for overcoming current limitations of the approach.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.forename: Brian
authors.initials: B
authors.lastname: Kuhlman
authors.forename: Tanja
authors.initials: T
authors.lastname: Kortemme
authors.forename: David
authors.initials: D
authors.lastname: Baker
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry; D019151:Peptide Library; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D011506:Proteins / Q000737:chemistry; D040901:Proteomics / Q000379:methods*; D012997:Solvents / Q000737:chemistry; D055672:Static Electricity; D013696:Temperature; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D019151:Peptide Library; D011506:Proteins; D012997:Solvents; D014867:Water; D009584:Nitrogen