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

Abstract

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.

Authors:
 [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
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Science Foundation (NSF); National Institutes of Health (NIH); Howard Hughes Medical Inst., Chevy Chase, MD (United States)
OSTI Identifier:
1436332
Alternate Identifier(s):
OSTI ID: 1401278
Grant/Contract Number:  
AC02-05CH11231; 1152196
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Angewandte Chemie (International Edition)
Additional Journal Information:
Journal Name: Angewandte Chemie (International Edition); Journal Volume: 56; Journal Issue: 14; Journal ID: ISSN 1433-7851
Publisher:
Wiley
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; enthalpy–entropy compensation; hydrophobic effects; mutational analysis; protein–ligand interactions

Citation Formats

Fox, Jerome M., Kang, Kyungtae, Sastry, Madhavi, Sherman, Woody, Sankaran, Banumathi, Zwart, Peter H., and Whitesides, George M. Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase. United States: N. p., 2017. Web. doi:10.1002/anie.201609409.
Fox, Jerome M., Kang, Kyungtae, Sastry, Madhavi, Sherman, Woody, Sankaran, Banumathi, Zwart, Peter H., & Whitesides, George M. Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase. United States. doi:10.1002/anie.201609409.
Fox, Jerome M., Kang, Kyungtae, Sastry, Madhavi, Sherman, Woody, Sankaran, Banumathi, Zwart, Peter H., and Whitesides, George M. Thu . "Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase". United States. doi:10.1002/anie.201609409. https://www.osti.gov/servlets/purl/1436332.
@article{osti_1436332,
title = {Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase},
author = {Fox, Jerome M. and Kang, Kyungtae and Sastry, Madhavi and Sherman, Woody and Sankaran, Banumathi and Zwart, Peter H. and Whitesides, George M.},
abstractNote = {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.},
doi = {10.1002/anie.201609409},
journal = {Angewandte Chemie (International Edition)},
number = 14,
volume = 56,
place = {United States},
year = {Thu Mar 02 00:00:00 EST 2017},
month = {Thu Mar 02 00:00:00 EST 2017}
}

Journal Article:
Free Publicly Available Full Text
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Cited by: 9 works
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