Water‐Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase

Journal Article · 02 March 2017 · Angewandte Chemie

DOI: https://doi.org/10.1002/ange.201609409 · OSTI ID:1401281

Fox, Jerome M. ^[1]; Kang, Kyungtae ^[1]; Sastry, Madhavi ^[2]; Sherman, Woody ^[3]; Sankaran, Banumathi ^[4]; Zwart, Peter H. ^[4]; Whitesides, George M. ^[1]

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

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.

• Sponsoring Organization: USDOE
• OSTI ID: 1401281
• Journal Information: Angewandte Chemie, Journal Name: Angewandte Chemie Vol. 129 Journal Issue: 14; ISSN 0044-8249
• Publisher: Wiley Blackwell (John Wiley & Sons)Copyright Statement
• Country of Publication: Germany
• Language: English