Water‐Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase

• Published in: Angewandte Chemie (International ed.) 2017-03, Vol.56 (14), p.3833-3837
• Main Authors: Fox, Jerome M., Kang, Kyungtae, Sastry, Madhavi, Sherman, Woody, Sankaran, Banumathi, Zwart, Peter H., Whitesides, George M.
• Format: Article
• Language: English
• Subjects: BASIC BIOLOGICAL SCIENCES; Binding; Binding Sites; Bonding strength; Carbonic anhydrase; Carbonic Anhydrase II - chemistry; Carbonic Anhydrase II - metabolism; Carbonic anhydrases; Crystallography; Enthalpy; enthalpy–entropy compensation; Entropy; Humans; Hydrogen bonding; Hydrogen bonds; Hydrophobic and Hydrophilic Interactions; hydrophobic effects; Hydrophobicity; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Ligands; Models, Molecular; Molecular Conformation; Mutants; Mutation; mutational analysis; Proteins; protein–ligand interactions; Thermodynamics; Water - chemistry; Water - metabolism
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201609409

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. Water in a binding pocket: The effect of water‐restructuring mutations on the thermodynamics of protein–ligand association is studied. Empirical and theoretical results suggest that mutations, by changing the thermodynamic properties of water in the binding pocket of human carbonic anhydrase II, can reverse the thermodynamic signature, and significantly alter the strength, of ligand binding.