Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase
Open Access
- 19 October 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (44), 17889-17894
- https://doi.org/10.1073/pnas.1114107108
Abstract
The hydrophobic effect—a rationalization of the insolubility of nonpolar molecules in water—is centrally important to biomolecular recognition. Despite extensive research devoted to the hydrophobic effect, its molecular mechanisms remain controversial, and there are still no reliably predictive models for its role in protein–ligand binding. Here we describe a particularly well-defined system of protein and ligands—carbonic anhydrase and a series of structurally homologous heterocyclic aromatic sulfonamides—that we use to characterize hydrophobic interactions thermodynamically and structurally. In binding to this structurally rigid protein, a set of ligands (also defined to be structurally rigid) shows the expected gain in binding free energy as hydrophobic surface area is added. Isothermal titration calorimetry demonstrates that enthalpy determines these increases in binding affinity, and that changes in the heat capacity of binding are negative. X-ray crystallography and molecular dynamics simulations are compatible with the proposal that the differences in binding between the homologous ligands stem from changes in the number and organization of water molecules localized in the active site in the bound complexes, rather than (or perhaps in addition to) release of structured water from the apposed hydrophobic surfaces. These results support the hypothesis that structured water molecules—including both the molecules of water displaced by the ligands and those reorganized upon ligand binding—determine the thermodynamics of binding of these ligands at the active site of the protein. Hydrophobic effects in various contexts have different structural and thermodynamic origins, although all may be manifestations of the differences in characteristics of bulk water and water close to hydrophobic surfaces.Keywords
This publication has 51 references indexed in Scilit:
- Fluoroalkyl and Alkyl Chains Have Similar Hydrophobicities in Binding to the “Hydrophobic Wall” of Carbonic AnhydraseJournal of the American Chemical Society, 2011
- Ligand binding to protein-binding pockets with wet and dry regionsProceedings of the National Academy of Sciences of the United States of America, 2011
- How Can Hydrophobic Association Be Enthalpy Driven?Journal of Chemical Theory and Computation, 2010
- Comparison of Entropic Contributions to Binding in a “Hydrophilic” versus “Hydrophobic” Ligand−Protein InteractionJournal of the American Chemical Society, 2010
- High‐energy water sites determine peptide binding affinity and specificity of PDZ domainsProtein Science, 2009
- Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand BindingChemical Reviews, 2008
- Hydrophobicity of protein surfaces: Separating geometry from chemistryProceedings of the National Academy of Sciences of the United States of America, 2008
- Motifs for molecular recognition exploiting hydrophobic enclosure in protein–ligand bindingProceedings of the National Academy of Sciences of the United States of America, 2007
- Interfaces and the driving force of hydrophobic assemblyNature, 2005
- Inhomogeneous Fluid Approach to Solvation Thermodynamics. 1. TheoryThe Journal of Physical Chemistry B, 1998