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Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase.
Angew Chem Int Ed Engl 2017; 56(14):3833-3837AC

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.

Authors+Show Affiliations

Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.Schrödinger, Sanali Infopark, 8-2-120/113 Banjara Hills, Hyderabad, 11937, Andhra Pradesh, India.Schrödinger, Inc., 120 West 45thStreet, New York, NY, 10036, USA.Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

28252841

Citation

Fox, Jerome M., et al. "Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase." Angewandte Chemie (International Ed. in English), vol. 56, no. 14, 2017, pp. 3833-3837.
Fox JM, Kang K, Sastry M, et al. Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase. Angew Chem Int Ed Engl. 2017;56(14):3833-3837.
Fox, J. M., Kang, K., Sastry, M., Sherman, W., Sankaran, B., Zwart, P. H., & Whitesides, G. M. (2017). Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase. Angewandte Chemie (International Ed. in English), 56(14), pp. 3833-3837. doi:10.1002/anie.201609409.
Fox JM, et al. Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase. Angew Chem Int Ed Engl. 2017 03 27;56(14):3833-3837. PubMed PMID: 28252841.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase. AU - Fox,Jerome M, AU - Kang,Kyungtae, AU - Sastry,Madhavi, AU - Sherman,Woody, AU - Sankaran,Banumathi, AU - Zwart,Peter H, AU - Whitesides,George M, Y1 - 2017/03/02/ PY - 2016/09/26/received PY - 2016/12/21/revised PY - 2017/3/3/pubmed PY - 2019/1/17/medline PY - 2017/3/3/entrez KW - enthalpy-entropy compensation KW - hydrophobic effects KW - mutational analysis KW - protein-ligand interactions SP - 3833 EP - 3837 JF - Angewandte Chemie (International ed. in English) JO - Angew. Chem. Int. Ed. Engl. VL - 56 IS - 14 N2 - 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. SN - 1521-3773 UR - https://www.unboundmedicine.com/medline/citation/28252841/Water_Restructuring_Mutations_Can_Reverse_the_Thermodynamic_Signature_of_Ligand_Binding_to_Human_Carbonic_Anhydrase_ L2 - https://doi.org/10.1002/anie.201609409 DB - PRIME DP - Unbound Medicine ER -