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:
-
- Harvard Univ., Cambridge, MA (United States). Dept. of Chemistry and Chemical Biology
- Schrodinger LLC, Pradesh (India)
- Schrodinger LLC, New York, NY (United States)
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- 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)
- OSTI Identifier:
- 1436332
- Alternate Identifier(s):
- OSTI ID: 1401278
- Grant/Contract Number:
- AC02-05CH11231; 1152196
- Resource Type:
- 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. https://doi.org/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. https://doi.org/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}
}
Web of Science
Works referenced in this record:
Thermodynamics of Binding of 2-Methoxy-3-isopropylpyrazine and 2-Methoxy-3-isobutylpyrazine to the Major Urinary Protein
journal, February 2004
- Bingham, Richard J.; Findlay, John B. C.; Hsieh, Shih-Yang
- Journal of the American Chemical Society, Vol. 126, Issue 6
Ligand Binding Stepwise Disrupts Water Network in Thrombin: Enthalpic and Entropic Changes Reveal Classical Hydrophobic Effect
journal, June 2012
- Biela, Adam; Sielaff, Frank; Terwesten, Felix
- Journal of Medicinal Chemistry, Vol. 55, Issue 13
Rational Approaches to Improving Selectivity in Drug Design
journal, January 2012
- Huggins, David J.; Sherman, Woody; Tidor, Bruce
- Journal of Medicinal Chemistry, Vol. 55, Issue 4
Modeling Water, the Hydrophobic Effect, and Ion Solvation
journal, June 2005
- Dill, Ken A.; Truskett, Thomas M.; Vlachy, Vojko
- Annual Review of Biophysics and Biomolecular Structure, Vol. 34, Issue 1
Wechselwirkungen mit aromatischen Ringen in chemischen und biologischen Erkennungsprozessen
journal, March 2003
- Meyer, Emmanuel A.; Castellano, Ronald K.; Diederich, François
- Angewandte Chemie, Vol. 115, Issue 11
Dissecting the Hydrophobic Effect on the Molecular Level: The Role of Water, Enthalpy, and Entropy in Ligand Binding to Thermolysin
journal, January 2013
- Biela, Adam; Nasief, Nader N.; Betz, Michael
- Angewandte Chemie International Edition, Vol. 52, Issue 6
Protein activity regulation by conformational entropy
journal, July 2012
- Tzeng, Shiou-Ru; Kalodimos, Charalampos G.
- Nature, Vol. 488, Issue 7410
Water-Mediated Recognition of Simple Alkyl Chains by Heart-Type Fatty-Acid-Binding Protein
journal, December 2014
- Matsuoka, Shigeru; Sugiyama, Shigeru; Matsuoka, Daisuke
- Angewandte Chemie, Vol. 127, Issue 5
Is it the shape of the cavity, or the shape of the water in the cavity?
journal, May 2013
- Snyder, Phillip W.; Lockett, Matthew R.; Moustakas, Demetri T.
- The European Physical Journal Special Topics, Vol. 223, Issue 5
Van der Waals Interactions Dominate Ligand−Protein Association in a Protein Binding Site Occluded from Solvent Water
journal, August 2005
- Barratt, Elizabeth; Bingham, Richard J.; Warner, Daniel J.
- Journal of the American Chemical Society, Vol. 127, Issue 33
Interfaces and the driving force of hydrophobic assembly
journal, September 2005
- Chandler, David
- Nature, Vol. 437, Issue 7059
Displacement of disordered water molecules from hydrophobic pocket creates enthalpic signature: Binding of phosphonamidate to the S1'-pocket of thermolysin
journal, November 2010
- Englert, L.; Biela, A.; Zayed, M.
- Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1800, Issue 11
Substrate Shape Determines Specificity of Recognition for HIV-1 Protease
journal, March 2002
- Prabu-Jeyabalan, Moses; Nalivaika, Ellen; Schiffer, Celia A.
- Structure, Vol. 10, Issue 3
Win some, lose some: enthalpy-entropy compensation in weak intermolecular interactions
journal, November 1995
- Dunitz, Jack D.
- Chemistry & Biology, Vol. 2, Issue 11
Water, water everywhere — except where it matters?
journal, July 2007
- Homans, S.
- Drug Discovery Today, Vol. 12, Issue 13-14
Interactions with Aromatic Rings in Chemical and Biological Recognition
journal, March 2003
- Meyer, Emmanuel A.; Castellano, Ronald K.; Diederich, François
- Angewandte Chemie International Edition, Vol. 42, Issue 11
Water Networks Contribute to Enthalpy/Entropy Compensation in Protein–Ligand Binding
journal, October 2013
- Breiten, Benjamin; Lockett, Matthew R.; Sherman, Woody
- Journal of the American Chemical Society, Vol. 135, Issue 41
Role of the Active-Site Solvent in the Thermodynamics of Factor Xa Ligand Binding
journal, March 2008
- Abel, Robert; Young, Tom; Farid, Ramy
- Journal of the American Chemical Society, Vol. 130, Issue 9
The RAS-Binding Domain of Human BRAF Protein Serine/Threonine Kinase Exhibits Allosteric Conformational Changes upon Binding HRAS
journal, August 2015
- Aramini, James M.; Vorobiev, Sergey M.; Tuberty, Lynda M.
- Structure, Vol. 23, Issue 8
Kinetic and Structural Insights into the Mechanism of Binding of Sulfonamides to Human Carbonic Anhydrase by Computational and Experimental Studies
journal, January 2016
- Gaspari, Roberto; Rechlin, Chris; Heine, Andreas
- Journal of Medicinal Chemistry, Vol. 59, Issue 9
Classification of Water Molecules in Protein Binding Sites
journal, March 2007
- Barillari, Caterina; Taylor, Justine; Viner, Russell
- Journal of the American Chemical Society, Vol. 129, Issue 9
A Two-State Model of Hydrophobic Hydration That Produces Compensating Enthalpy and Entropy Changes
journal, January 1996
- Lee, B.; Graziano, Giuseppe
- Journal of the American Chemical Society, Vol. 118, Issue 22
Water-Mediated Recognition of Simple Alkyl Chains by Heart-Type Fatty-Acid-Binding Protein
journal, December 2014
- Matsuoka, Shigeru; Sugiyama, Shigeru; Matsuoka, Daisuke
- Angewandte Chemie International Edition, Vol. 54, Issue 5
High-energy water sites determine peptide binding affinity and specificity of PDZ domains
journal, August 2009
- Beuming, Thijs; Farid, Ramy; Sherman, Woody
- Protein Science, Vol. 18, Issue 8
Enthalpy−Entropy Compensation: A Phantom or Something Useful?
journal, December 2007
- Starikov, Evgeni B.; Nordén, Bengt
- The Journal of Physical Chemistry B, Vol. 111, Issue 51
Inhomogeneous Fluid Approach to Solvation Thermodynamics. 1. Theory
journal, April 1998
- Lazaridis, Themis
- The Journal of Physical Chemistry B, Vol. 102, Issue 18
Inhomogeneous Fluid Approach to Solvation Thermodynamics. 2. Applications to Simple Fluids
journal, April 1998
- Lazaridis, Themis
- The Journal of Physical Chemistry B, Vol. 102, Issue 18
Adding calorimetric data to decision making in lead discovery: a hot tip
journal, December 2009
- Ladbury, John E.; Klebe, Gerhard; Freire, Ernesto
- Nature Reviews Drug Discovery, Vol. 9, Issue 1
Free Energy, Entropy, and Enthalpy of a Water Molecule in Various Protein Environments
journal, September 2010
- Yu, Hongtao; Rick, Steven W.
- The Journal of Physical Chemistry B, Vol. 114, Issue 35
Applying thermodynamic profiling in lead finding and optimization
journal, January 2015
- Klebe, Gerhard
- Nature Reviews Drug Discovery, Vol. 14, Issue 2
Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase
journal, October 2011
- Snyder, P. W.; Mecinovic, J.; Moustakas, D. T.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 44
How Can Hydrophobic Association Be Enthalpy Driven?
journal, August 2010
- Setny, Piotr; Baron, Riccardo; McCammon, J. Andrew
- Journal of Chemical Theory and Computation, Vol. 6, Issue 9
Motifs for molecular recognition exploiting hydrophobic enclosure in protein–ligand binding
journal, January 2007
- Young, Tom; Abel, Robert; Kim, Byungchan
- Proceedings of the National Academy of Sciences, Vol. 104, Issue 3
Methyl, Ethyl, Propyl, Butyl: Futile But Not for Water, as the Correlation of Structure and Thermodynamic Signature Shows in a Congeneric Series of Thermolysin Inhibitors
journal, March 2014
- Krimmer, Stefan G.; Betz, Michael; Heine, Andreas
- ChemMedChem, Vol. 9, Issue 4
Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand Binding
journal, March 2008
- Krishnamurthy, Vijay M.; Kaufman, George K.; Urbach, Adam R.
- Chemical Reviews, Vol. 108, Issue 3
Zerlegung des hydrophoben Effekts auf molekularer Ebene: Die Rolle von Wasser, Enthalpie und Entropie bei der Ligandenbindung an Thermolysin
journal, January 2013
- Biela, Adam; Nasief, Nader N.; Betz, Michael
- Angewandte Chemie, Vol. 125, Issue 6
Water-Mediated Hydrophobic Interactions
journal, May 2016
- Ben-Amotz, Dor
- Annual Review of Physical Chemistry, Vol. 67, Issue 1
Ligand binding to protein-binding pockets with wet and dry regions
journal, January 2011
- Wang, L.; Berne, B. J.; Friesner, R. A.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 4
Works referencing / citing this record:
Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC
journal, October 2018
- Krammer, Eva-Maria; Gibbons, Andrew; Roos, Goedele
- Scientific Reports, Vol. 8, Issue 1
Effective lead optimization targeting the displacement of bridging receptor–ligand water molecules
journal, January 2018
- Chen, Deliang; Li, Yibao; Zhao, Mingming
- Physical Chemistry Chemical Physics, Vol. 20, Issue 37
Wetting the lock and key enthalpically favours polyelectrolyte binding
journal, January 2019
- Jeamet, Emeric; Septavaux, Jean; Héloin, Alexandre
- Chemical Science, Vol. 10, Issue 1
Switched reaction specificity in polyesterases towards amide bond hydrolysis by enzyme engineering
journal, January 2019
- Biundo, Antonino; Subagia, Raditya; Maurer, Michael
- RSC Advances, Vol. 9, Issue 62
Molecular Basis of the Activation and Dissociation of Dimeric PYL2 Receptor in Abscisic Acid Signaling
posted_content, April 2021
- Zhao, Chuankai; Shukla, Diwakar
Molecular basis of the activation and dissociation of dimeric PYL2 receptor in abscisic acid signaling
journal, January 2022
- Zhao, Chuankai; Shukla, Diwakar
- Physical Chemistry Chemical Physics, Vol. 24, Issue 2
Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC
journal, October 2018
- Krammer, Eva-Maria; Gibbons, Andrew; Roos, Goedele
- Scientific Reports, Vol. 8, Issue 1
Crystal structure correlations with the intrinsic thermodynamics of human carbonic anhydrase inhibitor binding
text, January 2018
- Smirnov, Alexey; Zubrienė, Asta; Manakova, Elena
- Deutsches Elektronen-Synchrotron, DESY, Hamburg
Exploring Solanum tuberosum Epoxide Hydrolase Internal Architecture by Water Molecules Tracking
journal, November 2018
- Mitusińska, Karolina; Magdziarz, Tomasz; Bzówka, Maria
- Biomolecules, Vol. 8, Issue 4