Residual Ligand Entropy in the Binding of p-Substituted Benzenesulfonamide Ligands to Bovine Carbonic Anhydrase II

Henning Stckmann†‡, Agnieszka Bronowska†, Neil R. Syme†, Gary S. Thompson†, Arnout P. Kalverda, Stuart L. Warriner†‡ and Steve W. Homans†
Astbury Centre for Structural Molecular Biology and School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
J. Am. Chem. Soc., 2008, 130 (37), pp 12420–12426
DOI: 10.1021/ja803755m
Publication Date (Web): August 22, 2008
Copyright © 2008 American Chemical Society
†

Astbury Centre for Structural Molecular Biology.

,
‡

School of Chemistry.

,
s.w.homans@leeds.ac.uk
ACS AuthorChoice

Abstract

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In studies on the thermodynamics of ligand−protein interactions, it is often assumed that the configurational and conformational entropy of the ligand is zero in the bound state (i.e., the ligand is rigidly fixed in the binding pocket). However, there is little direct experimental evidence for this assumption, and in the case of binding of p-substituted benzenesulfonamide inhibitors to bovine carbonic anhydrase II (BCA II), the observed thermodynamic binding signature derived from isothermal titration calorimetry experiments leads indirectly to the conclusion that a considerable degree of residual entropy remains in the bound ligand. Specifically, the entropy of binding increases with glycine chain length n, and strong evidence exists that this thermodynamic signature is not driven by solvent reorganization. By use of heteronuclear 15N NMR relaxation measurements in a series (n = 1−6) of 15N-glycine-enriched ligands, we find that the observed thermodynamic binding signature cannot be explained by residual ligand dynamics in the bound state, but rather results from the indirect influence of ligand chain length on protein dynamics.

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History

  • Published In Issue September 17, 2008
  • Article ASAPAugust 22, 2008
  • Received: April 4, 2008

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