title: Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase.
abstract: This study uses mutants of human carbonic anhydrase (HCAII) to examine how changes in the organization of water within a binding pocket can alter the thermodynamics of protein-ligand association. Results from calorimetric, crystallographic, and theoretical analyses suggest that most mutations strengthen networks of water-mediated hydrogen bonds and reduce binding affinity by increasing the enthalpic cost and, to a lesser extent, the entropic benefit of rearranging those networks during binding. The organization of water within a binding pocket can thus determine whether the hydrophobic interactions in which it engages are enthalpy-driven or entropy-driven. Our findings highlight a possible asymmetry in protein-ligand association by suggesting that, within the confines of the binding pocket of HCAII, binding events associated with enthalpically favorable rearrangements of water are stronger than those associated with entropically favorable ones.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.
authors.forename: Jerome M
authors.initials: JM
authors.lastname: Fox
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.
authors.forename: Kyungtae
authors.initials: K
authors.lastname: Kang
authors.affiliation: Schrödinger, Sanali Infopark, 8-2-120/113 Banjara Hills, Hyderabad, 11937, Andhra Pradesh, India.
authors.forename: Madhavi
authors.initials: M
authors.lastname: Sastry
authors.affiliation: Schrödinger, Inc., 120 West 45thStreet, New York, NY, 10036, USA.
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
authors.affiliation: Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
authors.forename: Banumathi
authors.initials: B
authors.lastname: Sankaran
authors.affiliation: Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Zwart
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Whitesides
mesh_terms: D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D013816:Thermodynamics; D014867:Water / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D014867:Water; D024402:Carbonic Anhydrase II
keywords: enthalpy-entropy compensation; hydrophobic effects; mutational analysis; protein-ligand interactions