Interactions between Hofmeister Anions and the Binding Pocket of a Protein

Abstract

This paper uses the binding pocket of human carbonic anhydrase II (HCAII, EC 4.2.1.1) as a tool to examine the properties of Hofmeister anions that determine (i) where, and how strongly, they associate with concavities on the surfaces of proteins and (ii) how, upon binding, they alter the structure of water within those concavities. Results from X-ray crystallography and isothermal titration calorimetry show that most anions associate with the binding pocket of HCAII by forming inner-sphere ion pairs with the Zn 2+ cofactor. In these ion pairs, the free energy of anion−Zn 2+ association is inversely proportional to the free energetic cost of anion dehydration; this relationship is consistent with the mechanism of ion pair formation suggested by the "law of matching water affinities". Iodide and bromide anions also associate with a hydrophobic declivity in the wall of the binding pocket. Molecular dynamics simulations suggest that anions, upon associating with Zn 2+ , trigger rearrangements of water that extend up to 8 Å away from their surfaces. These findings expand the range of interactions previously thought to occur between ions and proteins by suggesting that (i) weakly hydrated anions can bind complementarily shaped hydrophobic declivities, and that (ii) ion-induced rearrangements of water within protein concavities can (in contrast with similar rearrangements in bulk water) extend well beyond the first hydration shells of the ions that trigger them. This study paints a picture of Hofmeister anions as a set of structurally varied ligands that differ in size, shape, and affinity for water and, thus, in their ability to bind toand to alter the charge and hydration structure ofpolar, nonpolar, and topographically complex concavities on the surfaces of proteins.

Structural Basis for Different Substrate Profiles of Two Closely Related Class D β-Lactamases and Their Inhibition by Halogens

“…Additionally, iodide ions are more tolerant to a hydrophobic environment than chloride ions and are found in hydrophobic patches of proteins. 62–64 Tyr141 from the YGN conserved motif that has been implicated in chloride inhibition of OXA-enzymes is 10Å away from the iodide in OXA-163 suggesting it has a minimal role in the binding of the iodide. 24 …”

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

“…2) Ionic strength; it is becoming increasingly apparent that relatively polarizable anions have an affinity for non-polar surfaces. 15 Thus, both the ionic strength and the nature of the electrolyte are important in shaping the hydrophobic effect. 3) Solute shape; from computational and experimental studies, it is evident that the solvation of convex, flat, and concave surfaces are different.…”

“…However, it is becoming increasingly evident that these areas do in fact frequently overlap; two prime examples being the accumulation of large polarizable anions at the air-water interface, 1-5 and the favorable interactions of polarizable anions with non-polar surfaces. [6][7][8][9][10][11][12][13][14][15] Thus the hydrophobic and Hofmeister effects are but part of a greater continuum of aqueous supramolecular chemistry, with many important and outstanding questions regarding the influence of the different kinds of non-covalent interactions involved.Studies of water and aqueous solutions have mostly been driven by the physical sciences community, a broad range of scientists whose expertise in spectroscopy, computer modeling, and biochemistry (to name just three areas) has generally not involved macrocycles or host molecules in general. However, for some time now, supramolecular chemists -with their expertise in macrocyclic synthesis and measuring weak non-covalent interactions -have been travelling a parallel course of exploration.…”

Physical‐Organic Chemistry: A Swiss Army Knife

“…Theory has led experiment in suggesting that the restructuring of the networks of water molecules in the active site of a protein, and around a lowmolecular weight ligand, influence-and, in many cases, dominate-the binding of that ligand and protein (Fig. 7) [76,[80][81][82] . This view, of course, is quite different from the physical-organic concepts of "docking," "lock and key," and "protein-ligand interactions."…”

“…We elaborate on the use of sialosides in the design of polyvalent inhibitors of the influenza-mediated clumping of cells in reference [111] . [82] . Figure 8.…”