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Water‐Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase
Author(s) -
Fox Jerome M.,
Kang Kyungtae,
Sastry Madhavi,
Sherman Woody,
Sankaran Banumathi,
Zwart Peter H.,
Whitesides George M.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201609409
Subject(s) - carbonic anhydrase ii , hydrogen bond , enthalpy , carbonic anhydrase , chemistry , entropy (arrow of time) , mutant , ligand (biochemistry) , solvation , plasma protein binding , crystallography , thermodynamics , biochemistry , enzyme , molecule , gene , receptor , organic chemistry , solvent , physics
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.