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



  • AbstractThis 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.

publication date

  • March 27, 2017

has restriction

  • green

Date in CU Experts

  • January 31, 2018 1:59 AM

Full Author List

  • Fox JM; Kang K; Sastry M; Sherman W; Sankaran B; Zwart PH; Whitesides GM

author count

  • 7

Other Profiles

International Standard Serial Number (ISSN)

  • 0044-8249

Electronic International Standard Serial Number (EISSN)

  • 1521-3757

Additional Document Info

start page

  • 3891

end page

  • 3895


  • 129


  • 14