Interactions between macromolecules and ions: the Hofmeister series

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The Hofmeister series, first noted in 1888, ranks the relative influence of ions on the physical behavior of a wide variety of aqueous processes ranging from colloidal assembly to protein folding. Originally, it was thought that an ion's influence on macromolecular properties was caused at least in part by ‘making’ or ‘breaking’ bulk water structure. Recent time-resolved and thermodynamic studies of water molecules in salt solutions, however, demonstrate that bulk water structure is not central to the Hofmeister effect. Instead, models are being developed that depend upon direct ion–macromolecule interactions as well as interactions with water molecules in the first hydration shell of the macromolecule.

Introduction

Specific ion effects are ubiquitous in chemistry and biology. Such effects exhibit a reoccurring trend called the Hofmeister series [1, 2], which is generally more pronounced for anions than for cations. The typical ordering of the anion series and some of its related properties are shown in Figure 1. The species to the left of Cl are referred to as kosmotropes, while those to its right are called chaotropes. These terms originally referred to an ion's ability to alter the hydrogen bonding network of water (Figure 2a) [3]. The kosmotropes, which were believed to be ‘water structure makers’, are strongly hydrated and have stabilizing and salting-out effects on proteins and macromolecules. On the other hand, chaotropes (‘water structure breakers’) are known to destabilize folded proteins and give rise to salting-in behavior.

Recently, substantial attention has been paid to Hofmeister phenomena because of their relevance to a broad range of fields. A few examples of physical behavior obeying the Hofmeister series include enzyme activity [4, 5, 6, 7], protein stability [8], protein–protein interactions [9, 10], protein crystallization [11], optical rotation of sugar and amino acids [12], as well as bacterial growth [13]. Although Hofmeister effects for macromolecules in aqueous solution are ubiquitous, the molecular-level mechanisms by which ions operate are only beginning to be unraveled [14••].

In this short review we first examine several recent experiments which cast doubt on the notion that water structure making and breaking by salts is central to the Hofmeister series. This leads to the hypothesis that direct ion–macromolecule interactions are largely responsible for most aspects of this phenomenon (Figure 2b). Second, we look at the inclusion of dispersion forces in theoretical calculations of specific ion effects. Finally, we describe a recent study on the lower critical solution temperature of poly(N-isopropylacrylamide). This final example employs a model that only involves direct ion interactions with a macromolecule and its first hydration shell to explain hydrophobic collapse.

Section snippets

Ions do not affect the bulk water properties

To investigate the influence of anions on aqueous solution structure, Bakker and co-workers [15••, 16, 17, 18, 19, 20] measured the orientational correlation time for water molecules in salt solutions by means of femtosecond two-color pump-probe spectroscopy. The Osingle bondH stretch mode of water molecules was excited with an intense ultrafast mid-infrared pulse and the dynamics of the excitation were followed using a second, weaker mid-infrared probe. The dynamic behavior of water molecules in the

Dispersion forces need to be taken into account

Derjaguin–Landau–Verwey–Overbeek (DLVO) theory of interparticle interactions treats colloid stability in terms of a balance of attractive van der Waals forces and repulsive electrical double-layer forces [30]. One of the major approximations in DLVO theory is the use of the Poisson–Boltzmann equation to describe the electrostatic interactions. This method treats ions in solution as point charges, and consequently, ion specificity is lost. DLVO theory works rather well at low salt concentrations

Ion effects on the solubility of poly(N-isopropylacrylamide)

Hydrophobic collapse of polymers and proteins is of central interest in Hofmeister phenomena because it represents a key step in protein folding. To explore hydrophobic collapse, our laboratory [47••] has monitored the lower critical solution temperature (LCST) of poly(N-isopropylacrylamide) (PNIPAM), a thermoresponsive polymer that becomes insoluble upon heating in aqueous solution [48, 49]. The LCST behavior of PNIPAM is essentially analogous to the cold denaturation/renaturation point of

Conclusion

Recent advances in understanding the mechanism of the Hofmeister series have provided valuable insights for several ion-specific phenomena. Experimental evidence clearly shows that changes in bulk water structure by added salts cannot explain specific ion effects. Instead, Hofmeister phenomena need to be understood in terms of direct interactions between the ions and macromolecules.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by the National Science Foundation (CHE-0094332) and the Robert A Welch Foundation (Grant A-1421).

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