(706c) Ion-Induced Perturbations of Solvation Structure Reverse the Thermodynamic Mechanism of Hydrophobic Association Between Human Carbonic Anhydrase and Arylsulfonamides

Authors: 
Fox, J. M. - Presenter, University of Colorado, Boulder
Whitesides, G. M., Harvard University
Kang, K., Harvard University

The hydrophobic effect—the tendency of nonpolar solutes to aggregate in aqueous solution, and the driving force of many biomolecular recognition events—arises from the energetically favorable rearrangement of molecules of water.  A detailed understanding of the mechanism by which these rearrangements alter the thermodynamics of ligand-protein interactions is essential for (i) predicting the thermodynamic influence of conditions that alter solvation structure (e.g. the presence of other solutes, structural changes in interacting species) and for (ii) exploiting the hydrophobic effect in the rational design of tight-binding ligands.  In this work, we studied the thermodynamic repercussions of incremental perturbations to solvation structure by examining the influence of Hofmeister anions on the thermodynamics of hydrophobic interactions between Human Carbonic Anhydrase II (HCA, EC 4.2.11) and arylsulfonamide ligands.  Using a combination of calorimetry, x-ray crystallography, and molecular dynamics simulations, we show that chaotropes displace the zinc-bound water inside the active site of HCAII, triggering rearrangements in networks of water that give rise to large and nearly compensating changes in the enthalpy and entropy of binding.  These changes scale with the surface tension increment of these ions and, eventually, give rise to an entropically dominated hydrophobic effect that differs dramatically from the enthalpically dominated effect that governs HCAII-arylsulfonamide association in the absence of Hofmeister anions.  We will discuss the implications of these results for existing theories of hydrophobic ligand-protein interactions.