Anion Binding to Ammonium and Guanidinium Hosts: Implications for the Reverse Hofmeister Effects Induced by Lysine and Arginine Residues

Authors: Jordan, Jacobs; GIBB, CORINNE - Tulane University; TRAN, THIEN - Tulane University; YAO, WEI - Tulane University; ROSE, AUSTIN - Tulane University; MAGUE, JOEL - Tulane University; Easson, Michael; GIBB, BRUCE - Tulane University

Submitted to: Journal of Organic Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/11/2024
Publication Date: 4/25/2024
Citation: Jordan, J.H., Gibb, C.L., Tran, T., Yao, W., Rose, A., Mague, J.T., Easson, M.W., Gibb, B.C. 2024. Anion Binding to Ammonium and Guanidinium Hosts: Implications for the Reverse Hofmeister Effects Induced by Lysine and Arginine Residues. Journal of Organic Chemistry. https://doi.org/10.1021/acs.joc.4c00242.
DOI: https://doi.org/10.1021/acs.joc.4c00242

Interpretive Summary: The data presented here yield several key findings. First, they emphasize the multitude interactions that guanidiniums can form, and how — at least qualitatively — this repertoire far surpasses that of ammoniums. Second, they reveal the ability of anions to dispense with hydration shell waters, rearrange those that remain, and form direct contacts with hosts. In other words, given a positive electrostatic potential field, even charge-dense ions can partially lose waters of hydration and nestle into non-polar ‘nooks and crannies’. This picture is in sharp contrast to the commonly conceived idea of all-or-nothing anion solvation; a concept that in our mind handicaps progress in both aqueous supramolecular chemistry and Hofmeister studies. The partial desolvation or solvent shell plasticity model does however highlight many open questions. Namely, how does this affects the aggregation of solutes at high anion concentrations. These topics are discussed to provide information to those studying solute properties in water.

Technical Abstract: The nature of anions has a profound effect on the properties of proteins, these so-called anionic Hofmeister effects have implications in biologics stability, protein aggregation, amyloidogenesis, crystallization, and more generally, the properties of any water-based host-guest systems. However, the inter-play of the key supramolecular interactions responsible for Hofmeister effects is poorly understood. To contribute to improving this state-of-affairs, we report here on the supramolecular interactions between anions and ammonium and guanidinium groups and their consequences. Specifically, we investigate the properties of cavitand hosts that mimic two prime areas for anion-protein interactions: lysine and arginine residues. Thus, we report NMR and ITC affinity studies, X-ray structural analysis, MD simulations, as well as critical precipitation concentration values for the weak associations between of anions and tetra-ammonium and tetra-guanidinium cavitands 1 and 2. Our findings emphasize the multitude of non-covalent interactions that guanidiniums can form, and how — at least qualitatively — this repertoire surpasses that of ammoniums. Additionally, our studies reveal the ability of anions to dispense with labile hydration-shell waters, rearrange those that remain, and form direct non-covalent contacts with hosts. This partial desolvation or solvent shell plasticity model is in sharp contrast to the commonly concept of all-or-nothing anion solvation, and highlights many questions concerning how this adaptability varies as a function of the nature of the anion, how the energetics of this process impacts the different supramolecular motifs between anions and ammoniums/guanidiniums, and how this affects the aggregation of solutes at high anion concentrations. These topics are discussed to provide information to those studying solute properties in water.