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Title: Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase

Journal Article · · Angewandte Chemie (International Edition)
 [1];  [1];  [2];  [3];  [4];  [4];  [1]
  1. Harvard Univ., Cambridge, MA (United States). Dept. of Chemistry and Chemical Biology
  2. Schrodinger LLC, Pradesh (India)
  3. Schrodinger LLC, New York, NY (United States)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology
+ Show Author Affiliations

In this study we use 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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF); National Institutes of Health (NIH); Howard Hughes Medical Inst., Chevy Chase, MD (United States)
Grant/Contract Number:
AC02-05CH11231; 1152196
OSTI ID:
1436332
Alternate ID(s):
OSTI ID: 1401278
Journal Information:
Angewandte Chemie (International Edition), Vol. 56, Issue 14; ISSN 1433-7851
Publisher:
WileyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 25 works
Citation information provided by
Web of Science

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Cited By (8)

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC journal October 2018
Effective lead optimization targeting the displacement of bridging receptor–ligand water molecules journal January 2018
Wetting the lock and key enthalpically favours polyelectrolyte binding journal January 2019
Switched reaction specificity in polyesterases towards amide bond hydrolysis by enzyme engineering journal January 2019
Molecular Basis of the Activation and Dissociation of Dimeric PYL2 Receptor in Abscisic Acid Signaling posted_content April 2021
Molecular basis of the activation and dissociation of dimeric PYL2 receptor in abscisic acid signaling journal January 2022
Crystal structure correlations with the intrinsic thermodynamics of human carbonic anhydrase inhibitor binding text January 2018
Exploring Solanum tuberosum Epoxide Hydrolase Internal Architecture by Water Molecules Tracking journal November 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
enthalpy–entropy compensation
hydrophobic effects
mutational analysis
protein–ligand interactions