Format

Send to

Choose Destination
Angew Chem Int Ed Engl. 2017 Mar 27;56(14):3833-3837. doi: 10.1002/anie.201609409. Epub 2017 Mar 2.

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

Author information

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 45thStreet, 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.

KEYWORDS:

enthalpy-entropy compensation; hydrophobic effects; mutational analysis; protein-ligand interactions

PMID:
28252841
DOI:
10.1002/anie.201609409
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Wiley Icon for eScholarship, California Digital Library, University of California
Loading ...
Support Center