Interactions Between Macromolecules and Ions: the Hofmeister Series Yanjie Zhang and Paul S Cremer

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Interactions between macromolecules and ions: the Hofmeister series Yanjie Zhang and Paul S Cremer

The Hofmeister series, first noted in 1888, ranks the relative [4–7], protein stability [8], protein–protein interactions influence of ions on the physical behavior of a wide variety of [9,10], protein crystallization [11], optical rotation of sugar aqueous processes ranging from colloidal assembly to protein and amino acids [12], as well as bacterial growth [13]. folding. Originally, it was thought that an ion’s influence on Although Hofmeister effects for macromolecules in aqu- macromolecular properties was caused at least in part by eous solution are ubiquitous, the molecular-level mechan- ‘making’ or ‘breaking’ bulk water structure. Recent time- isms by which ions operate are only beginning to be resolved and thermodynamic studies of water molecules in salt unraveled [14]. solutions, however, demonstrate that bulk water structure is not central to the Hofmeister effect. Instead, models are being In this short review we first examine several recent experi- developed that depend upon direct ion–macromolecule ments which cast doubt on the notion that water structure interactions as well as interactions with water molecules in the making and breaking by salts is central to the Hofmeister first hydration shell of the macromolecule. series. This leads to the hypothesis that direct ion–macromolecule interactions are largely responsible for most Addresses Department of Chemistry, Texas A&M University, College Station, TX aspects of this phenomenon (Figure 2b). Second, we look 77843, USA at the inclusion of dispersion forces in theoretical calcula- tions of specific ion effects. Finally, we describe a recent Corresponding author: Cremer, Paul S ([email protected]) study on the lower critical solution temperature of poly(N- isopropylacrylamide). This final example employs a model Current Opinion in Chemical Biology 2006, 10:1–6 that only involves direct ion interactions with a macromolecule and its first hydration shell to explain hydrophobic This review comes from a themed issue on Biopolymers collapse. Edited by Hagan P Bayley and Floyd Romesberg Ions do not affect the bulk water properties To investigate the influence of anions on aqueous solution 1367-5931/$ – see front matter structure, Bakker and co-workers [15 ,16–20] measured # 2006 Elsevier Ltd. All rights reserved. the orientational correlation time for water molecules in salt solutions by means of femtosecond two-color DOI 10.1016/j.cbpa.2006.09.020 pump-probe spectroscopy. The O–H stretch mode of water molecules was excited with an intense ultrafast mid-infrared pulse and the dynamics of the excitation were Introduction followed using a second, weaker mid-infrared probe. The Specific ion effects are ubiquitous in chemistry and dynamic behavior of water molecules in the liquid could be biology. Such effects exhibit a reoccurring trend called observed on time scales shorter than the exchange time the Hofmeister series [1,2], which is generally more between water in the ion solvation shell and in the bulk pronounced for anions than for cations. The typical liquid. The results showed that correlation times for first ordering of the anion series and some of its related hydration shell water molecules of Cl ,Br ,I , ClO4 or 2 properties are shown in Figure 1. The species to the left SO4 were much slower than those for bulk water, as of Cl are referred to as kosmotropes, while those to its might be expected. The experiments, however, clearly right are called chaotropes. These terms originally demonstrated that these anions had no influence on the referred to an ion’s ability to alter the hydrogen bonding dynamics of bulk water, even at very high concentrations 2 network of water (Figure 2a) [3]. The kosmotropes, which (up to 6 M) of both kosmotropic ions (SO4 ) and chao- were believed to be ‘water structure makers’, are strongly tropic ions (ClO4 )[15 ]. In other words, the anions did hydrated and have stabilizing and salting-out effects on not alter the hydrogen bonding network outside the direct proteins and macromolecules. On the other hand, chao- vicinity of the anion. As a result, it was concluded that no tropes (‘water structure breakers’) are known to destabi- long-range structure-making or structure-breaking effects lize folded proteins and give rise to salting-in behavior. for either kosmotropes or chaotropes take place. These experiments provided a crucial challenge to the notion that Recently, substantial attention has been paid to Hofme- salt solutions affect bulk water structure. ister phenomena because of their relevance to a broad range of fields. A few examples of physical behavior A second challenge to bulk water structure ‘making’ and obeying the Hofmeister series include enzyme activity ‘breaking’ theories came from thermodynamic studies by www.sciencedirect.com Current Opinion in Chemical Biology 2006, 10:1–6

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2 Biopolymers

Figure 1

The Hofmeister series. Adapted from: http://tinyurl.com/ed5gj with permission.

Pielak et al. [21]. Bulk water can be conceptualized as a stabilizers and denaturants. Data were collected as a func- mixture of two rapidly interconverting species: a less tion of temperature to provide the coefficient of thermal dense, more structured form, and a more dense, less expansion a ¼ 1=Vð@V=@TÞ p, where V is the partial molar structured arrangement [22]. This two-state mixture specific volume. Measuring a simplified the determination approximation has proven useful in understanding the of ð@C p=@PÞT by using the Maxwell relation: volumetric properties of solutions. It has therefore been assumed that the difference between bulk water and @C p @ðVaÞ hydration water arises from the varying ratio between these ¼T @P T @T P two forms. Specifically, a ‘structure-making’ solute should increase the fraction of the less dense architecture at the A total of 17 solutes (including guanidinium ions and expense of the more dense form in the solute’s hydration urea) were chosen for their well-known stabilizing or water. On the other hand, a ‘structure-breaking’ solute destabilizing effects on proteins. The results showed should have the opposite effect. The sign of ð@C p=@PÞT , no obvious correlation between known stability effects where C p represents the partial molar constant pressure and the sign of ð@C p=@PÞT . Thus, the notion of stabilizers heat capacity, indicates whether a solute makes and denaturants as bulk water structure makers and

[ð@C p=@PÞT < 0] or breaks [ð@C p=@PÞT > 0] water structure breakers seems to be disproved on thermodynamic as [23]. To probe this, Pielak and co-workers employed well as spectroscopic grounds. pressure perturbation calorimetry, which measures the heat transfer resulting from a pressure change above the In a third series of experiments, Cremer et al. [24] sample solution. The resultant sign of ð@C p=@PÞT and its directly followed the inﬂuence of Hofmeister anions on temperature dependence should therefore provide a direct the phase transition of a surfactant monolayer while probe of structure making and breaking properties of simultaneously observing the adjacent water structure.

Figure 2

Anions and water structure. (a) Organized water beyond an anion’ first hydration shell would be needed for structure-making and breaking effects to occur. (b) The direct interaction of an anion with a macromolecule in aqueous solution. The relative sizes of water molecules, macromolecules, and the anion are not generally to scale. However, the relative size of the anion with respect to the water molecules is 2 approximately correct for SO4 .

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Interactions between macromolecules and ions: the Hofmeister series Zhang and Cremer 3

In this case, an octadecylamine monolayer was spread on alkyl chain ordering comes from Leontidis et al. [29]. salt solutions at the air/water interface and monitored by These researchers demonstrated that chaotropic anions using vibrational sum frequency spectroscopy (VSFS). could penetrate a lipid monolayer. They investigated a VSFS can provide crucial information because it is cap- DPPC (1,2-dipalmitoyl phosphatidylcholine) film at the able of examining interfacial water structure as well as the air/salt solution interface. The monolayer phase behavior, ordering of the surfactant molecules. Specifically, VSFS is morphology and structure of the lipid phase were inter- sensitive to alkyl chain conformation in the monolayer rogated by surface pressure-area isotherm measurements, [25] and can be exploited to ascertain the propensity of Brewster angle microscopy, grazing incidence X-ray any given anion to induce gauche defects into the film’s diffraction, and infrared reflection-absorption spectro- alkyl chains under constant temperature and pressure scopy. The presence of chaotropic salts in the subphase conditions. Vibrational spectra were collected from mono- increased the surface pressure at a fixed area per mole- layers spread on D2O subphases containing various cule. The magnitude of this increase followed the order of sodium salts. The ratio of the oscillator strengths from Hofmeister series: Cl < Br < NO3 < I < BF4 < the methyl symmetric stretch and the methylene sym- ClO4 < SCN . Therefore, at least for Langmuir mono- metric stretch was obtained for each anion. The higher layers, it is the direct interactions of the ions with the film this ratio, the more ordered the monolayer is under a that are primarily responsible for the observed changes in given set of conditions [25,26]. The ratios for the anions physical behavior, not indirect influences via changes in followed the Hofmeister series from most ordered to least water structure. 2 ordered monolayer as: SO4 > Cl > NO3 > Br > I > ClO4 > SCN . The basis for this ordering is Dispersion forces need to be taken into related to an individual anion’s ability to penetrate the account headgroup region of the monolayer, thereby disrupting Derjaguin–Landau–Verwey–Overbeek (DLVO) theory the hydrocarbon packing (Figure 3)[27,28]. These results of interparticle interactions treats colloid stability in terms showed excellent correlation with complementary surface of a balance of attractive van der Waals forces and potential measurements made under the same conditions. repulsive electrical double-layer forces [30]. One of the Next, the interfacial water structure was probed under major approximations in DLVO theory is the use of the nearly identical conditions, but with H2O rather than Poisson–Boltzmann equation to describe the electrostatic D2O in the subphase. The water structure data showed interactions. This method treats ions in solution as point a partial Hofmeister-like trend, but had significant devia- charges, and consequently, ion specificity is lost. DLVO tions from the series. For example, a high degree of water theory works rather well at low salt concentrations (up to ordering was seen in the presence of ClO4 , but not 0.01 M), where electrostatic forces dominate. The the- SCN. The observed differences between the way anions ory, however, loses its validity at salt concentrations of affected alkyl chain ordering and surface potential on the biological interest or in any system where the ion con- one hand and water structure on the other further argues centration approaches 0.1 M or higher. To help remedy against the hypothesis that the Hofmeister effect is this problem, Ninham et al. [31,32] have recently intro- primarily due to the ions’ ability to influence bulk water duced a dispersion potential into DLVO theory and structure. treated it at the same level as the electrostatic forces. By using this modified model, specific ion effects on the Additional corroboration for the idea that anion penetra- interactions between charged particles could be exam- tion into a Langmuir film is responsible for changes in ined. These authors have now employed their model to help interpret many ion-specific phenomena, including Figure 3 lysozyme behavior in salt solutions [33], ion binding to micelles [34], counterion condensation on polyelectrolytes [35], pH measurements in buffers and protein solutions [36–38], as well as the surface tension of electrolytes [39,40]. Moreover, Jungwirth and Tobias [41– 43,44] have performed simulations of air/electrolyte interfaces in the presence of salt in which they included the ions’ polarizabilities. Figure 4 shows sample ion distributions from aqueous/air interfaces at 1.2 M sodium halide solutions obtained by molecular dynamics simulations. This elegant work clearly shows that including polarizability is critical to obtaining the correct ion dis- An octadecylamine monolayer at the air/salt solution interface. The tribution as a function of distance from the interface as arrows compare the penetration of kosmotropic (green) and chaotropic (red) anions into the headgroup region of the monolayer. The red x found by high pressure X-ray photoelectron spectroscopy indicates that the kosmotrope doesn’t effectively penetrate into the experiments [45]. On the other hand, Manciu and headgroup region. Ruckenstein [46 ], have cast doubt on the ability of www.sciencedirect.com Current Opinion in Chemical Biology 2006, 10:1–6

4 Biopolymers

Figure 4

Top and side views of aqueous/air interfaces for 1.2 M sodium halide solutions obtained by molecular dynamics simulations. adding a polarizability term to correctly predict all inter- shell. First, kosmotropic anions were found to polarize facial properties at the aqueous/water interface in the water molecules that were directly hydrogen bonded with presence of salts. Also, Kunz et al. have found that that the amide moieties of PNIPAM (Figure 5a). Second, both including polarizability to describe ion effects at the chaotropes and kosmotropes could increase the cost of protein/water interface is less important than at the air/ hydrophobic hydration (i.e. raise the surface tension of water interface [7]. the polymer/water interface; Figure 5b). Third, chaotropic anions could bind directly to the side-chain amide Ion effects on the solubility of poly(N- moieties (Figure 5c). The first and second of these isopropylacrylamide) interactions led to the salting-out of the polymer- thereby Hydrophobic collapse of polymers and proteins is of lowering the LCST, whereas the third effect causes the central interest in Hofmeister phenomena because it polymer to salt-in. Moreover, the first two phenomena represents a key step in protein folding. To explore depend linearly on salt concentration [50] whereas the hydrophobic collapse, our laboratory [47] has monitored third displays simple saturation behavior. These facts the lower critical solution temperature (LCST) of poly(N- allowed us to model the perturbation of PNIPAM’s isopropylacrylamide) (PNIPAM), a thermoresponsive LCST by added salts using a simple equation that con- polymer that becomes insoluble upon heating in aqueous sists of a constant, a linear term, and a Langmuir isotherm: solution [48,49]. The LCST behavior of PNIPAM is essentially analogous to the cold denaturation/renatura- BmaxKA½M T ¼ T 0 þ c½Mþ tion point of proteins. The sodium salts of 11 anions 1 þ KA½M were studied and the ability of a particular anion to lower the LCST followed the Hofmeister series. Significantly, T0 is the LCST of PNIPAM in the absence of salt and [M] the effect of the anions could be completely explained on is the molar concentration of salt. The constant, c, has the basis of three direct interactions of the anions with the units of temperature/molarity. KA is the binding constant macromolecule and its immediately adjacent hydration of the anion to the polymer and Bmax is the increase in the

Figure 5

Interactions amongst anions, PNIPAM, and hydration waters. (a) Hydrogen bonding of the amide and its destabilization through polarization by the anion, X. (b) The hydrophobic hydration of the macromolecule, which can be modulated by salt. (c) Direct binding of the anion to the amide moiety of PNIPAM.

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Interactions between macromolecules and ions: the Hofmeister series Zhang and Cremer 5

5. Pinna MC, Salis A, Monduzzi M, Ninham BW: Hofmeister series: phase transition temperature due to direct ion binding at the hydrolytic activity of Aspergillus niger lipase depends on saturation. Using this equation, it could be shown that an specific anion effects. J Phys Chem B 2005, 109:5406-5408. anion’s effect on the LCST correlated extremely well to 6. Bauduin P, Nohmie F, Touraud D, Neueder R, Kunz W, its hydration entropy (DShydr), surface tension increment Ninham BW: Hofmeister specific-ion effects on enzyme activity and buffer pH: Horseradish peroxidase in citrate buffer. (s), and binding constant, KA. Moreover, only kosmo- J Mol Liq 2006, 123:14-19. tropes showed a correlation between the slope, c, of the 7. Vrbka L, Jungwirth P, Bauduin P, Touraud D, Kunz W: Specific ion LCST and DShydr (note: polarization of water is related to effects at protein surfaces: a molecular dynamics study of water ordering). On the other hand, the chaotropes bovine pancreatic trypsin inhibitor and horseradish peroxidase showed excellent correlation between c and the value in selected salt solutions. J Phys Chem B 2006, 110:7036-7043. of s. Hence, it could be shown that the mechanisms of 8. Broering JM, Bommarius AS: Evaluation of Hofmeister effects on the kinetic stability of proteins. J Phys Chem B 2005, action of the chaotropes and kosmotropes were funda- 109:20612-20619. mentally different in modulating the LCST. These 9. Perez-Jimenez R, Godoy-Ruiz R, Ibarra-Molero B, results indicate that, in certain instances, chaotropes Sanchez-Ruiz JM: The efficiency of different salts to screen and kosmotropes work by separate mechanisms rather charge interactions in proteins: A Hofmeister effect? Biophys J 2004, 86:2414-2429. than on a continuously graded scale. 10. Curtis RA, Lue L: A molecular approach to bioseparations: protein-protein and protein-salt interactions. Chem Eng Sci It should be pointed out that a preliminary understanding 2006, 61:907-923. of the influence of anions on the physical properties of 11. Collins KD: Ions from the Hofmeister series and osmolytes: macromolecules is really only a first step toward under- effects on proteins in solution and in the crystallization standing the effects of solution conditions on biological process. Methods 2004, 34:300-311. systems. A complete picture will inevitably involve an 12. Lo Nostro P, Ninham BW, Milani S, Fratoni L, Baglioni P: Specific anion effects on the optical rotation of glucose and serine. integrated understanding of the role of cations (including Biopolymers 2006, 81:136-148. guanidinium ions) and osmolytes (such as urea and tri- 13. Lo Nostro P, Ninham BW, Lo Nostro A, Pesavento G, Fratoni L, methylamine N-oxide) as well. There has been some Baglioni P: Specific ion effects on the growth rates of progress in these fields, although such subjects are gen- Staphylococcus aureus and Pseudomonas aeruginosa. erally beyond the scope of this short review. Phys Biol 2005, 2:1-7. 14. Kunz W, Lo Nostro P, Ninham BW: The present state of affairs with Hofffieister effects. Curr Opin Colloid Interface Sci 2004, Conclusion 9:1-18. Recent advances in understanding the mechanism of the This review describes recent research on the Hofmeister series. Hofmeister series have provided valuable insights for 15. Omta AW, Kropman MF, Woutersen S, Bakker HJ: Negligible several ion-specific phenomena. Experimental evidence effect of ions on the hydrogen-bond structure in liquid water. Science 2003, 301:347-349. clearly shows that changes in bulk water structure by added This paper describes dynamic measurements of water molecules in salt salts cannot explain specific ion effects. Instead, Hofme- solutions by using femtosecond mid-infrared pump-probe spectroscopy. It is shown directly for the first time that water structure outside the ister phenomena need to be understood in terms of direct hydration shell of an ion is not influenced by the ion. This result is valid for interactions between the ions and macromolecules. both kosmotropic ions and chaotropic ions. 16. Kropman MF, Bakker HJ: Effect of ions on the vibrational Acknowledgements relaxation of liquid water. J Am Chem Soc 2004, 126:9135-9141. This work was supported by the National Science Foundation (CHE- 17. Kropman MF, Bakker HJ: Vibrational relaxation of liquid water in 0094332) and the Robert A Welch Foundation (Grant A-1421). ionic solvation shells. Chem Phys Lett 2003, 370:741-746. 18. Omta AW, Kropman MF, Woutersen S, Bakker HJ: Influence of References and recommended reading ions on the hydrogen-bond structure in liquid water. 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