1. Water‐Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase
- Author
-
Fox, Jerome M, Kang, Kyungtae, Sastry, Madhavi, Sherman, Woody, Sankaran, Banumathi, Zwart, Peter H, and Whitesides, George M
- Subjects
Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Binding Sites ,Carbonic Anhydrase II ,Humans ,Hydrophobic and Hydrophilic Interactions ,Ligands ,Models ,Molecular ,Molecular Conformation ,Mutation ,Thermodynamics ,Water ,enthalpy-entropy compensation ,hydrophobic effects ,mutational analysis ,protein-ligand interactions ,Organic Chemistry ,Chemical sciences - 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.
- Published
- 2017