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Arginine and the Hofmeister Series: the role of ion-ion interactions in protein aggregation suppression.

ABSTRACT: L-Arginine hydrochloride is a very important aggregation suppressor for which there has been much attention given regarding elucidating its mechanism of action. Little consideration, however, has been given toward other salt forms besides chloride, even though the counterion likely imparts a large influence per the Hofmeister Series. Here, we report an in depth analysis of the role the counterion plays in the aggregation suppression behavior of arginine. Consistent with the empirical Hofmeister series, we found that the aggregation suppression ability of other arginine salt forms on a model protein (?-chymotrypsinogen) follows the order: H(2)PO(4)(-) > SO(4)(2-) > citrate(2-) > acetate(-) ? F(-) ? Cl(-) > Br(-) > I(-) ? SCN(-). Mechanistically, preferential interaction and osmotic virial coefficient measurements, in addition to molecular dynamics simulations, indicate that attractive ion-ion interactions, particularly attractive interactions between arginine molecules, play a dominate role in the observed behavior. Furthermore, it appears that dihydrogen phosphate, sulfate, and citrate have strong attractive interactions with the guanidinium group of arginine, which seems to contribute to the superior aggregation suppression ability of those salt forms by bridging together multiple arginine molecules into clusters. These results not only further our understanding of how arginine influences protein stability, they also help to elucidate the mechanism behind the Hofmeister Series. This should help to improve biopharmaceutical stabilization through the use of other arginine salts and possibly, the development of novel excipients.

SUBMITTER: Schneider CP

PROVIDER: S-EPMC3110691 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Arginine and the Hofmeister Series: the role of ion-ion interactions in protein aggregation suppression.

Schneider Curtiss P CP Shukla Diwakar D Trout Bernhardt L BL

The journal of physical chemistry. B 20110513 22

L-Arginine hydrochloride is a very important aggregation suppressor for which there has been much attention given regarding elucidating its mechanism of action. Little consideration, however, has been given toward other salt forms besides chloride, even though the counterion likely imparts a large influence per the Hofmeister Series. Here, we report an in depth analysis of the role the counterion plays in the aggregation suppression behavior of arginine. Consistent with the empirical Hofmeister ...[more]

PMID: 21568311

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Project description:Quantitative interpretation and prediction of Hofmeister ion effects on protein processes, including folding and crystallization, have been elusive goals of a century of research. Here, a quantitative thermodynamic analysis, developed to treat noncoulombic interactions of solutes with biopolymer surface and recently extended to analyze the effects of Hofmeister salts on the surface tension of water, is applied to literature solubility data for small hydrocarbons and model peptides. This analysis allows us to obtain a minimum estimate of the hydration b1 (H2O A(-2)), of hydrocarbon surface and partition coefficients Kp, characterizing the distribution of salts and salt ions between this hydration water and bulk water. Assuming that Na+ and SO4(2-) ions of Na2SO4 (the salt giving the largest reduction in hydrocarbon solubility as well as the largest increase in surface tension) are fully excluded from the hydration water at hydrocarbon surface, we obtain the same b1 as for air-water surface (approximately 0.18 H2O A(-2)). Rank orders of cation and anion partition coefficients for nonpolar surface follow the Hofmeister series for protein processes, but are strongly offset for cations in the direction of exclusion (preferential hydration). By applying a coarse-grained decomposition of water accessible surface area (ASA) into nonpolar, polar amide, and other polar surface and the same hydration b1 to interpret peptide solubility increments, we determine salt partition coefficients for amide surface. These partition coefficients are separated into single-ion contributions based on the observation that both Cl- and Na+ (also K+) occupy neutral positions in the middle of the anion and cation Hofmeister series for protein folding. Independent of this assignment, we find that all cations investigated are strongly accumulated at amide surface while most anions are excluded. Cation and anion effects are independent and additive, allowing successful prediction of Hofmeister salt effects on micelle formation and other processes from structural information (ASA).

Dataset Information

Arginine and the Hofmeister Series: the role of ion-ion interactions in protein aggregation suppression.

Publications

Arginine and the Hofmeister Series: the role of ion-ion interactions in protein aggregation suppression.

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