Neutron diffraction experiments were carried out on aqueous solutions containing either guanidinium or thiocyanate ions. The first-order difference method of neutron diffraction and isotopic substitution was applied, and the hydration structures of two of nature's strongest denaturant ions were determined. Each ion is shown to interact weakly with water: Guanidinium has no recognizable hydration shell and is one of the most weakly hydrated cations yet characterized. Hydration of thiocyanate is characterized by a low coordination number involving around one hydrogenbonded water molecule and approximately two water molecules weakly interacting through ''hydration bonds.'' The weak hydration of these denaturant ions strongly supports suggestions that a major contribution to the denaturant effect is the preferential interaction of the denaturant with the protein surface. By contrast, solute species such as many sugars and related polyols that stabilize proteins are strongly hydrated and are thus preferentially retained in the bulk solvent and excluded from the protein surface. J ust over a century ago, Hofmeister (1) arranged ions into a series based on their ability to salt out proteins. Since then, others have extended this approach and have used it to characterize the ability of particular ions to nature or denature biological material (2-5). In this article we provide convincing evidence from neutron diffraction and isotopic substitution experiments that, we believe, goes a significant way to rationalizing the differing behavior of certain ions in biological solution. We came to this conclusion by focusing on two of nature's strongest denaturant ions [guanidinium (Gdm ϩ ) and thiocyanate (SCN Ϫ )] and by referring to previously published results derived from neutron diffraction and isotopic substitution. The method was first introduced in the 1970s and has been used to obtain structural information at the atomic level around specific atoms and ions in solution (6). In contrast to other methods, it is formally exact and does not require sophisticated modeling procedures for the determination of properties, such as nearestneighbor coordination numbers and ion-water geometry.Specifically, the article addresses the question of what the differences are, if any, in the hydration structure of ions whose denaturation properties have been arranged in a series according to their ability to denature or stabilize proteins. The results we present below on the hydration structure of Gdm ϩ and SCN Ϫ have relevance to the mechanics of ion denaturation of biologically active material in aqueous electrolyte solution. The Gdm ϩ cation is the most powerful protein denaturant commonly used in studies of protein stability and folding (5), despite the fact that the detailed mechanism of its denaturation properties remains unresolved. Gdm ϩ ions bind to polypeptides, and this binding is expected to provide a significant contribution to protein denaturation because, on unfolding, many buried peptide backbone amides, hydrogen-bonded with...
The combination of neutron diffraction with isotopic substitution (NDIS) experiments and molecular dynamics (MD) simulations to characterize the structuring in an aqueous solution of the denaturant guanidinium chloride is described. The simulations and experiments were carried out at a concentration of 3 m at room temperature, allowing for an examination of any propensity for ion association in a realistic solution environment. The simulations satisfactorily reproduced the principal features of the neutron scattering and indicate a bimodal hydration of the guanidinium ions, with the N-H groups making well-ordered hydrogen bonds in the molecular plane, but with the planar faces relatively deficient in interactions with water. The most striking feature of these solutions is the rich ion-ion ordering observed around the guanidinium ion in the simulations. The marked tendency of the guanidinium ions to stack parallel to their water-deficient surfaces indicates that the efficiency of this ion as a denaturant is due to its ability to simultaneously interact favorably with both water and hydrophobic side chains of proteins.
Atomic ordering in network glasses on length scales longer than nearest-neighbour length scales has long been a source of controversy. Detailed experimental information is therefore necessary to understand both the network properties and the fundamentals of glass formation. Here we address the problem by investigating topological and chemical ordering in structurally disordered AX2 systems by applying the method of isotopic substitution in neutron diffraction to glassy ZnCl2. This system may be regarded as a prototypical ionic network forming glass, provided that ion polarization effects are taken into account, and has thus been the focus of much attention. By experiment, we show that both the topological and chemical ordering are described by two length scales at distances greater than nearest-neighbour length scales. One of these is associated with the intermediate range, as manifested by the appearance in the measured diffraction patterns of a first sharp diffraction peak at 1.09(3) A(-1); the other is associated with an extended range, which shows ordering in the glass out to 62(4) A. We also find that these general features are characteristic of glassy GeSe2, a prototypical covalently bonded network material. The results therefore offer structural insight into those length scales that determine many important aspects of supercooled liquid and glass phenomenology.
Calcium is one of the biologically most important ions; however, its accurate description by classical molecular dynamics simulations is complicated by strong electrostatic and polarization interactions with surroundings due to its divalent nature. Here, we explore the recently suggested approach for effectively accounting for polarization effects via ionic charge rescaling and develop a new and accurate parametrization of the calcium dication. Comparison to neutron scattering and viscosity measurements demonstrates that our model allows for an accurate description of concentrated aqueous calcium chloride solutions. The present model should find broad use in efficient and accurate modeling of calcium in aqueous environments, such as those encountered in biological and technological applications.
Molecular dynamics simulations show significant like-charge pairing of guanidinium side chains in aqueous poly-arginine, while this effect is absent in aqueous poly-lysine containing ammonium-terminated side chains. This behavior of the guanidinium group is revealed also by protein database searches, having important biochemical implications. Combination of molecular dynamics simulations with explicit solvent and ab initio calculations employing a polarizable continuum model of water allows one to rationalize the formation of contact ion pairs between guanidinium cations in terms of individual interactions at the molecular level.
SignificanceThe passive translocation mechanism of arginine-rich cell-penetrating peptides has puzzled the scientific community for more than 20 y. In this study we propose a hitherto unrecognized mechanism of passive cell entry involving fusion of multilamellar structures generated by the cell-penetrating peptides. The geometry of entry for this mechanism is completely different from previously suggested direct translocation mechanisms, leading to another paradigm for designing molecular carriers for drug delivery to the cell.
It is a textbook knowledge that charges of the same polarity repel each other. For two monovalent ions in the gas phase at a close contact this repulsive interaction amounts to hundreds of kilojoules per mole. In aqueous solutions, however, this Coulomb repulsion is strongly attenuated by a factor equal to the dielectric constant of the medium. The residual repulsion, which now amounts only to units of kilojoules per mole, may be in principle offset by attractive interactions. Probably the smallest cationic pair, where a combination of dispersion and cavitation forces overwhelms the Coulomb repulsion, consists of two guanidinium ions in water. Indeed, by a combination of molecular dynamics with electronic structure calculations and electrophoretic, as well as spectroscopic, experiments, we have demonstrated that aqueous guanidinium cations form (weakly) thermodynamically stable like-charge ion pairs. The importance of pairing of guanidinium cations in aqueous solutions goes beyond a mere physical curiosity, since it has significant biochemical implications. Guanidinium chloride is known to be an efficient and flexible protein denaturant. This is due to the ability of the orientationally amphiphilic guanidinium cations to disrupt various secondary structural motifs of proteins by pairing promiscuously with both hydrophobic and hydrophilic groups, including guanidinium-containing side chains of arginines. The fact that the cationic guanidinium moiety forms the dominant part of the arginine side chain implies that the like-charge ion pairing may also play a role for interactions between peptides and proteins. Indeed, arginine-arginine pairing has been frequently found in structural protein databases. In particular, when strengthened by a presence of negatively charged glutamate, aspartate, or C-terminal carboxylic groups, this binding motif helps to stabilize peptide or protein dimers and is also found in or near active sites of several enzymes. The like-charge pairing of the guanidinium side-chain groups may also hold the key to the understanding of the arginine "magic", that is, the extraordinary ability of arginine-rich polypeptides to passively penetrate across cellular membranes. Unlike polylysines, which are also highly cationic but lack the ease in crossing membranes, polyarginines do not exhibit mutual repulsion. Instead, they accumulate at the membrane, weaken it, and might eventually cross in a concerted, "train-like" manner. This behavior of arginine-rich cell penetrating peptides can be exploited when devising smart strategies how to deliver in a targeted way molecular cargos into the cell.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.