Water mediated ligand functional group cooperativity: the contribution of a methyl group to binding affinity is enhanced by a COO(-) group through changes in the structure and thermodynamics of the hydration waters of ligand-thermolysin complexes.
Ligand functional groups can modulate the contributions of one another to the ligand-protein binding thermodynamics, producing either positive or negative cooperativity. Data presented for four thermolysin phosphonamidate inhibitors demonstrate that the differential binding free energy and enthalpy caused by replacement of a H with a Me group, which binds in the well-hydrated S2' pocket, are more favorable in presence of a ligand carboxylate. The differential entropy is however less favorable. Dissection of these differential thermodynamic parameters, X-ray crystallography, and density-functional theory calculations suggest that these cooperativities are caused by variations in the thermodynamics of the complex hydration shell changes accompanying the H→Me replacement. Specifically, the COO(-) reduces both the enthalpic penalty and the entropic advantage of displacing water molecules from the S2' pocket and causes a subsequent acquisition of a more enthalpically, less entropically, favorable water network. This study contributes to understanding the important role water plays in ligand-protein binding.
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA. nnnasief@yahoo.com
Nader N
NN
Nasief
Hongwei
H
Tan
Jing
J
Kong
David
D
Hangauer
D001407:Bacillus / Q000737:chemistry; D002151:Calorimetry; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry; D018360:Crystallography, X-Ray; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D013237:Stereoisomerism; D013816:Thermodynamics; D013820:Thermolysin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D014867:Water / Q000737:chemistry*
D002264:Carboxylic Acids; D008024:Ligands; D063065:Organophosphonates; D014867:Water; D013820:Thermolysin