A Simple Theory for the Hofmeister Series - The Journal of Physical

Perspective pubs.acs.org/JPCL

A Simple Theory for the Hofmeister Series Wen Jun Xie and Yi Qin Gao* Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, Peking National Laboratory for Molecular Sciences, Peking University, Beijing 100871, China ABSTRACT: In cells, biological molecules function in an aqueous solution. Electrolytes and other small molecules play important roles in keeping the osmotic pressure of the cellular environment as well as the structure formation and function of biomolecules. The observed empirical rules such as Hofmeister series are still waiting for molecular interpretations. In this Perspective, we will discuss a simple and self-consistent theory that takes into account the cooperative effects of cations and anions in affecting water/air surface tension, water activity, and the solubility of model compounds including polypeptides. Molecular dynamics simulations used to test these theoretical models will also be discussed.

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ion cooperativity in understanding how salts affect water activity, although the additive effects of anions and cations were found to work for properties such as conductivity and diffusion constants. On the basis of the analysis of chromatography, Jones-Dole viscosity B coefficients, and solution neutron and Xray diffraction data, a rule of “matching water affinity” was found,11,12 which has strong indications on the cation−anion cooperativity of salt effects. In fact, such nonadditive behavior of ions can be seen from the activity coefficients of ions in aqueous solutions, which for many salts deviate from the limiting Debye−Hückel theory at concentrations as low as 0.1 M. For example, the activity coefficients given in Figure 1 show that the ranking order of the sodium and potassium salts varies with the anion, γNaF > γ KF, but γNaSCN < γ KSCN. Similarly, the ranking order of the alkali salts is quite different for salts containing PO43−, HPO42−, and H2PO4−,13 in a way consistent with the matching water affinity rule.

lectrolyte solutions play essential roles in life and physical sciences. Salts can strongly affect the behavior of other solutes such as macromolecules and nonpolar molecules in aqueous solutions.1,2 More than a century ago, Franz Hofmeister ranked the ions based on their salting-out ability on proteins.3,4 The series named after him was later found to be valid in salt effects on many other properties.5,6 The anionic Hofmeister series is generally written as CO32− > SO42−> F− > Cl− > Br− > I− ≈ NO3−, with the ions on the left-hand side called kosmotropes and those on the right-hand side chaotropes.7 The Hofmeister series has become the subject of a very active research area in recent years.8 It is generally accepted that ions affect the structure and dynamics of water, although to what extent such an effect exists is under debate. Kosmotropes and chaotropes are also called “structure makers” and “structure breakers”,9 respectively. However, the exact physical meaning of such terms is not unambiguous, the understanding of which is hindered by the complexities in the interactions among cations, anions, and water.10

Experimental data show that ion cooperativity may play an important role in affecting water properties. Quick Summary of Experimental Observations. Salt Activity Coefficients. A large number of experimental measurements have been dedicated to quantify the activity coefficients of salts in water. For most simple salts, their low-concentration activity coefficients can be accounted for by the Debye−Hückel theory. However, the explanation of these results at higher concentrations is nontrivial. Although a number of quasiempirical equations do exist, a unified physical model is still in need. In particular, we want to point out here the importance of © 2013 American Chemical Society

Figure 1. Salt activity coefficients of NaF, KF, NaSCN, and KSCN electrolyte solutions (data taken from ref 13). Received: September 26, 2013 Accepted: November 26, 2013 Published: November 26, 2013 4247

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where f is the activity coefficient of the solute and cs the molar concentration of the salt. When ks is positive, the addition of the cosolute reduces the solubility of the solute. The data in Table 1 follow the same anionic Hofmeister series, whereas the ranking orders for the cations show a strong dependence on the counterions. In addition, salts affect the solubility of the proteins and polypeptide ATGEE18 in a manner distinctly different from their effects on simple apolar molecules. These data again suggest that the effects of anions and cations are not additive, and therefore, cation/anion cooperativity should be considered. Self-Consistent and Simple Theoretical Model. Salt Effects on Surface Tension. First, using a simple continuum model that takes into account the electrostatic attraction between opposite charges and the corresponding depletion of solvation as a result of ion association, we showed that the probability of association of simple ions follows a trend similar to the matching water affinity rule.19 Molecular dynamics (MD) simulations using both simple fixed point charge and polarizable models also yielded similar conclusions. Cations and anions with the same ion size tend to form contact ion pairs (CIPs), with the conterions occupying significantly the first solvation shell of the central ion and reducing its hydration.20 Salts with different cation and anion hydration energies are more likely to form solvent-separated ion pairs (SSIP) than CIP. Furthermore, the preferred orientation of water molecules was observed at the water/air interface from MD simulations and attributed to the uneven positive and negative charge distribution in the water molecule.21 This charge distribution of water also contributes to the preferred surface adsorption of anions over cations.22 A simple theory of salt effects on the water/air surface tension was then formulated to account for the various effects mentioned above.19 In particular, the enrichment of anions over cations at the surface has a tendency of reducing the surface tension. Because preferred adsorption of cations has an opposite effect, such a charge distribution effect is attenuated by ion pairing. Taking into account the interactions of individual ions with water, the theory predicts that the order of surface tension enhancement by salts roughly follows a trend, in the form of (anion solvation energy, cation solvation energy) (strong, strong) ≈ (strong, weak) > (weak, weak) > (weak, strong). Depending on the couterion, the following different ranking orders, Li+ > Na+ > K+, Na+ > Li+ > K+, K+ > Li+ > Na+, or K+ > Na+ > Li+, can be observed for its effect on surface tension. On the other hand, as a result of ion pairing, consistent with the experimental observations, the activity coefficients are small for salts with (strong, strong) and (weak, weak) combinations. Solubilities of Amides. To understand how salts and other small molecules affect protein backbone solvation and protein secondary structure formation (the effects of the Hofmeister series on the solvation of side chains and hydrophobic contacts is not covered in this Perspective), it is instructive to first analyze the various interactions in the multicomponent system. We noticed the important role of the carbonyl group of the amide group, which is a good hydrogen bond acceptor. Next, we realized that the change of free hydrogen donor/acceptor availability has a direct effect on the hydration of amide. As shown in Figure 3a−c, cations and anions affect the hydrogenbonding hydrogen donor/acceptor equilibrium in bulk water, in opposite directions. In addition, ions may interact directly with

Salt Effects on the Water/Air Surface Tension. Salts also have significant ion-specific effects on the water/air surface tension. Normally, the ability of anions on increasing water/air surface tension follows the Hofmeister series, CO32− > SO42− > F− > Cl− > Br− > NO3− > I− > ClO4− > SCN−.14 However, when the preferred binding coefficient is calculated separately for cations and anions, one can see that the surface adsorption for the anions varies significantly with the counterions. More obviously, cations do not show a conserved ranking order.15,16 When the counterion is changed, the ranking order of alkali cations judged by the increase of the water/air surface tension can be significantly altered.14 For example, for chlorides, the ranking order is Na+ > K+ ≈ Li+, whereas for sulphates, this order changes to Li+ > Cs+ > Na+ > K+, and for iodides, it is K+ ≈ Na+ > Li+. These facts indicate that cation and anion effects in affecting the water surface tension are not simple additions of the two. In Figure 2, we summarize some surface tension data.

Figure 2. Experimental results of the salt effect on the water surface tension (taken from ref 14).

Salting-Out Coefficient. Another interesting ranking order of the Hofmeister series, which is related more directly to the original definition of this series, is based on how strongly salts affect protein solubility and structure formation. Numerous experimental measurements and excellent reviews exist in this area.17 It is beyond the scope of this Perspective to provide a thorough review on these data. In Table 1, we list, as examples, Table 1. Salt Effects on Setschenow Salting-Out Coefficients of Benzene and Amide Ca2+

Li+

Na+

K+

Cs+ a

Cl− Br− I− Cl− Br− I− a

benzene Setschenow salting-out coefficients 0.14 0.20 0.17 0.16 0.12 0.10 amide Setschenow salting-out coefficientsb −0.09 0.02 0.05 0.05 −0.36 −0.17 0.00 −0.02 −0.28 −0.23 −0.21

0.09 −0.01 0.06

In units of L/mol; from ref 2. bIn units of L/mol; from ref 18.

some experimental results on salt effects on the solubility of benzene and a model polypeptide, ATGEE. Following common notations, the effects of salts on solubility at low to medium concentrations are listed in this table in terms of the salting-out coefficient ks ln f = kscs

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Figure 3. Salt effects on the protein amide hydrogen bond. (a) The cation can “solvate” carbonyl directly or indirectly by increasing the availability of water hydrogen, (b) the strongly hydrated anion competes with the carbonyl for hydration, (c) the cation and anion have opposite effects on the hydrogen donor/acceptor equilibrium, and (d) hydrogen bond donor rich cosolutes act as a protein secondary structure denaturant, and hydrogen bond donor deficient cosolutes act as a protein secondary structure protectant.

those rich in proton acceptors have opposite effects and function as protein secondary structure denaturants and renaturants, respectively. For example, salts with strongly solvated hydrated cations and weakly solvated anions (e.g., MgI2 or even MgCl2) are expected to show a strong salting-in effect, whereas salts with opposite cation versus anion properties, such as K2SO4, should have a strong salting-out effect. Such expectations are consistent with experimental observations.17 Urea and Gdm+, two common denaturants, are both rich in hydrogen donors, and the increase of amide solvation by the denaturants again can be a result of both direct and indirect effects; the latter increases the free hydrogen bond donors of water.24,25 In contrast, addition of molecules acting mainly as hydrogen acceptors, such as alcohols, GB, and TMAO, desolvate the protein backbone and therefore enhance the secondary structure. These predictions are again consistent with the experimental observations as well as computer simulation studies.26,27 Finally, the theory predicts that proton-acceptor-rich cosolvents such as TMAO counteract the denaturing effects of proton-donor-rich molecules such as urea, which is again a well-known experimental observation. These cosolutes are summarized in Figure 3d, classified by their hydrogen bond donor/acceptor content.

the amide; cations can bind the carbonyl oxygen and anions to the hydrophobic side chain or the amino hydrogen. A simple theory was then proposed with ion binding to the amide and ion pairing included.23 In this theory, because the solvation of amide carbonyl plays a more important role than the amine hydrogen, as an approximation, we neglect in this model the solvation of the NH group. When it is taken into account that both “direct” and “indirect” binding of cations change the chemical potential of the amide,19 the salt dependence of the amide carbonyl activity coefficient is written as − RT

− RTνb1 ASA(1 + ε±) ⎧ ⎛ μ+ + μ− ⎞ d ln[− CO] ⎨exp⎜ − ⎟ ≈ ⎩ ⎝ d[ML] 2RT ⎠ m1* ⎫ ⎛ 1 μ+ − μ− ⎞ ⎟ − 1⎬ cosh⎜ ⎝ RT 2 + 4λ ⎠ ⎭ (2)

In the above equation, R is the gas constant, T is the temperature, [−CO] is the concentration of carbonyl, [ML] is the concentration of salt, m*1 is the molality of water, b1 is the number of water molecules per surface area at the surface, 1 + ε± is the factor that converts the concentration derivative to an activity derivative, ν = ν+ + ν− is the number of ions per formula unit of salt, ASA is the water accessible surface area, and μ+(r) and μ−(r) are the “local external potential” that resulted from the differences of ion solvation between the bulk and the surface at the infinite dilute salt concentration, which can also take into account effects of the preferential partition of ions, for example, the large anions, near the protein surface. λ represents the cooperativity of cations and anions, with λ = 0 as the non-cation−anion cooperativity. An instructive form of λ obtained from a simple Born model can be used here to qualitatively illustrate the important roles of ion cooperativity.19 After considering the preferential ion binding and exclusion to the protein backbone, it is shown generally that larger anions (smaller μ−) salt-in protein and smaller cations (larger μ+) tend to strongly salt-in or weakly salt-out protein. With the ion cooperativity, a minimum salting-in effect might appear for cations with intermediate size, which is consistent with experimental results on polypeptide ATGEE.18 One of the most important predictions of the theory is that at low concentrations, cosolutes rich in proton donors and

Changes of hydrogen donor/acceptor equilibrium by ions and small molecules correlate well with their effects on protein secondary structures. To further understand molecular details on how salts, small molecules, and water interact with proteins/polypeptides and affect their structures, MD simulations were performed. The structure of a polypeptide, BBA5, was studied in water and water/alcohol solutions (shown in Figure 4), and simulation results were tested by NMR measurements.26,27 It was found that all four alcohols, methanol, TFE, glycol, and glycerol, enhance the secondary structure formation and increase intramolecular hydrogen bonding of the polypeptide, although their effects on the hydrophobic interactions are very different. 4249

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In the current Perspective, we focused our discussions from a thermodynamic point of view on how salts and cosolvents affect the solvation of the polar protein backbone. As illustrated in Figure 3, the theory itself does not distinguish between direct and indirect binding of the added cosolutes or cosolvents to the protein. In fact, whether these effects of salts on water properties, such as hydrogen bonding structures and dynamics, and native protein structures is direct or indirect and whether these changes follow the Hofmeister series has caused much confusion. The ions’ impact on water structure (most noticeably its hydrogen bond network) varies with the length and time scales. The uncertainty and lack of understanding on exactly which structural and/or dynamical aspect is provided by the experimental techniques also exist. For water dynamics, earlier studies suggested that ions tend to affect only locally,34 such as in their first solvation shell,35 although a more recent study showed that certain salts can change water reorientation dynamics at a longer distance.36 The latter experimental observation was argued to be consistent with neutron diffraction,37 NMR,38 and viscosity measurements.12 Nevertheless, a lack of an integrated understanding of the ions’ influence on water dynamics may also suggest that salt effects are ion-specific. Further analyses of the experimental data are needed to understand how ion cooperativity affects water dynamics in aqueous solutions.39 However, thermodynamic data do provide important information that allows one to relate the solvation properties of ions and proteins/small molecules to the salt effects on the solutions. Our analysis showed that the often neglected cation− anion cooperativity plays a very important role in these effects. Ion pairing, as a particular form of ion cooperativity, may correlate directly with the effects of ions on water dynamics. The model also suggests that the protein secondary structure denaturants and protectants can exert their effects on protein structures through changing of the hydrogen bond donor/ acceptor balance in the aqueous solution, which further changes the solvation of the protein backbone. Although some calculations40 have shown that the binding energy between cations and the carbonyl can be significant, a recent study of Cremer and co-workers showed no evidence of apparent direct cation binding to the protein backbone.41 This study as well as earlier chromography and X-ray studies suggest a weak direct binding of cations and thus indicates the important roles of the indirect mechanism through which cations affect the hydrogen bond donor availability. Careful studies are still needed to establish the relation between the binding of cations to the carbonyl group.

Figure 4. The solution environment significantly affects the structure of BBA5; glycerol and Na2SO3 enhance BBA5 structure formation in similar ways, whereas methanol and NaI denature the structure in different ways. Methanol is in fact a secondary structure promoter; in contrast, NaI does not strongly perturb the hydrophobic interaction.

Methanol and TFE, but not glycol or glycerol, break the hydrophobic interactions and denature the polypeptide. Further, MD simulations on the B domain of protein A (BdpA) denaturation by GdmCl or GdmSCN revealed the effects of counterions on the denaturing efficiency of guanidinium.28 Owing to the weaker hydrogen-accepting capability of SCN− in comparison to Cl−, GdmSCN denatures the protein secondary structure more efficiently than GdmCl, as shown in the simulations. In GdmSCN, the hydrogen bonding from both water and Gdm+ play important roles in protein denaturation, whereas in GdmCl, the approach of Gdm+ to the protein surface is impeded by the ion pairing between Gdm+ and Cl−, reducing direct hydrogen bonding from Gdm+ to the protein backbone, and reconciles the differences observed on Gdm+ hydrogen binding in different studies.29−31 Such a counterion effect in cation binding to the amide was also observed in the simulation studies of salt effects on the structure and dynamics of BBA5 using a chaotrope NaI and a kosmotrope Na2SO3 as examples (shown in Figure 4).32 This latter study showed that the Na+ binding with the backbone carbonyl groups of BBA5 is much weaker in the Na2SO3 solution than that in the NaI solution as a result of strong ion association of the former and exclusion of SO32− from the protein surface. These studies also allowed us to test the hypothesis that the hydrogen bonding ability of water is changed by these cosolutes/cosolvents. The calculated free hydrogen donor/acceptor concentrations are consistent with the above argument. For example, GdmCl (GdmSCN) at the molar fraction of 0.12 changes the free hydrogen donor per water molecule from 0.46 to about 1.0 and decreases the acceptor concentration from 0.46 to about 0.1,28 whereas when CH3OH, a protein secondary structure protectant, is added at the molar fraction of 0.24, the average numbers of free hydrogen donors and acceptors per water molecule become 0.72 and 0.07, respectively.27 It was indeed found that the addition of protein secondary structure makers (e.g., TMAO, methanol, or a salt formed by a strongly hydrated anion and a more weakly hydrated cation such as K2SO4) increases the free hydrogen acceptors of water, while the addition of protein secondary structure breakers (such as GdmCl and GdmSCN, with the latter having a stronger effect) has an opposite effect.33

Further studies are needed to distinguish direct and indirect salt effects as well as salt effects on side-chain interactions. Anions, together with cations, form a salt and affect both protein secondary and tertiary structure. In MD simulations, large, highly polarizable anions tend to accumulate near the protein apolar surfaces and may play an important role in affecting protein structures. To fully understand salt effects on protein, further studies are needed to understand ion−water interactions42 and to reveal the molecular details on how salt ions interact with the protein backbone as well as with protein side chains of different polarity and charges. It would be also 4250

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(11) Collins, K. D. Charge Density-Dependent Strength of Hydration and Biological Structure. Biophys. J. 1997, 72, 65−76. (12) Collins, K. D. Ions from the Hofmeister Series and Osmolytes: Effects on Proteins in Solution and in the Crystallization Process. Methods 2004, 34, 300−311. (13) Robinson, R. A.; Stokes, R. H. Electrolyte Solutions; Dover Publications: New York, 2002. (14) Pegram, L. M.; Record, M. T. Hofmeister Salt Effects on Surface Tension Arise from Partitioning of Anions and Cations between Bulk Water and the Air−Water Interface. J. Phys. Chem. B 2007, 111, 5411− 5417. (15) Weissenborn, P. K.; Pugh, R. J. Surface Tension and Bubble Coalescence Phenomena of Aqueous Solutions of Electrolytes. Langmuir 1995, 11, 1422−1426. (16) Weissenborn, P. K.; Pugh, R. J. Surface Tension of Aqueous Solutions of Electrolytes: Relationship with Ion Hydration, Oxygen Solubility, and Bubble Coalescence. J. Colloid Interface Sci. 1996, 184, 550−563. (17) Timasheff, S. N.; Fasman, G. D. Structure and Stability of Biological Macromolecules; Dekker: New York, 1969. (18) Robinson, D. R.; Jencks, W. P. The Effect of Concentrated Salt Solutions on the Activity Coefficient of Acetyltetraglycine Ethyl Ester. J. Am. Chem. Soc. 1965, 87, 2470−2479. (19) Gao, Y. Q. Simple Theoretical Model for Ion Cooperativity in Aqueous Solutions of Simple Inorganic Salts and Its Effect on Water Surface Tension. J. Phys. Chem. B 2011, 115, 12466−12472. (20) Yang, L. J.; Fan, Y. B.; Gao, Y. Q. Differences of Cations and Anions: Their Hydration, Surface Adsorption, and Impact on Water Dynamics. J. Phys. Chem. B 2011, 115, 12456−12465. (21) Fan, Y. B.; Chen, X.; Yang, L. J.; Cremer, P. S.; Gao, Y. Q. On the Structure of Water at the Aqueous/Air Interface. J. Phys. Chem. B 2009, 113, 11672−11679. (22) Jungwirth, P.; Tobias, D. J. Molecular Structure of Salt Solutions: A New View of the Interface with Implications for Heterogeneous Atmospheric Chemistry. J. Phys. Chem. B 2001, 105, 10468−10472. (23) Gao, Y. Q. Simple Theory for Salt Effects on the Solubility of Amide. J. Phys. Chem. B 2012, 116, 9934−9943. (24) Yang, L.; Gao, Y. Q. Effects of Cosolvents on the Hydration of Carbon Nanotubes. J. Am. Chem. Soc. 2010, 132, 842−848. (25) Wei, H.; Fan, Y.; Gao, Y. Q. Effects of Urea, Tetramethyl Urea, and Trimethylamine N-Oxide on Aqueous Solution Structure and Solvation of Protein Backbones: A Molecular Dynamics Simulation Study. J. Phys. Chem. B 2010, 114, 557−568. (26) Hwang, S.; Shao, Q.; Williams, H.; Hilty, C.; Gao, Y. Q. Methanol Strengthens Hydrogen Bonds and Weakens Hydrophobic Interactions in Proteins  A Combined Molecular Dynamics and NMR Study. J. Phys. Chem. B 2011, 115, 6653−6660. (27) Shao, Q.; Fan, Y. B.; Yang, L. J.; Gao, Y. Q. From Protein Denaturant to Protectant: Comparative Molecular Dynamics Study of Alcohol/Protein Interactions. J. Chem. Phys. 2012, 136, 115101. (28) Shao, Q.; Fan, Y. B.; Yang, L. J.; Gao, Y. Q. Counterion Effects on the Denaturing Activity of Guanidinium Cation to Protein. J. Chem. Theory Comput. 2012, 8, 4364−4373. (29) Mason, P. E.; Neilson, G. W.; Enderby, J. E.; Saboungi, M.-L.; Dempsey, C. E.; MacKerell, A. D., Jr.; Brady, J. W. The Structure of Aqueous Guanidinium Chloride Solutions. J. Am. Chem. Soc. 2004, 126, 11462−11470. (30) O’Brien, E. P.; Dima, R. I.; Brooks, B.; Thirumalai, D. Interactions between Hydrophobic and Ionic Solutes in Aqueous Guanidinium Chloride and Urea Solutions: Lessons for Protein Denaturation Mechanism. J. Am. Chem. Soc. 2007, 129, 7346−7353. (31) Lim, W. K.; Rosgen, J.; Englander, S. W. Urea, But Not Guanidinium, Destabilizes Proteins by Forming Hydrogen Bonds to the Peptide Group. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 2595−2600. (32) Xie, W. J.; Gao, Y. Q. Ion Cooperativity and the Effect of Salts on Polypeptide Structure  A Molecular Dynamics Study of BBA5 in Salt Solutions. Faraday Discuss. 2013, 160, 191−206.

interesting to examine whether the simple rule found on protein backbone solvation can be applied to other biological and organic compounds, such as DNA, acetones, and amines.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Wen Jun Xie received his B.S. in Chemistry with a double major in Mathematics in 2012 from Peking University, under the direction of Professor Yi Qin Gao. He is currently a graduate student in Professor Gao’s group. Xie dedicates himself to investigating thermodynamics and dynamical properties of aqueous solutions. Yi Qin Gao received his B.S. from Sichuan University, conducting research with Changwei Hu, his M.S. from the Institute of Chemistry, Chinese Academy of Sciences, supervised by Dalin Yang, and his Ph.D from Caltech, working with Rudolph A. Marcus, all in chemistry. He then did postdoctoral research with Martin Karplus at Harvard University. He started his independent career at Texas A&M University and moved to Peking University as a Changjiang Professor in 2010. His lab is working in the field of theoretical and computational chemistry, developing efficient computational methods and statistical mechanics tools to study the conformations of biological molecules in aqueous solutions, mechanisms of enzymatic reactions, and the solvation effects in chemical reactions. Website: http://www. chem.pku.edu.cn/gaoyq/.

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ACKNOWLEDGMENTS Y.Q.G. is a 2008 Changjiang Scholar, and he thanks NSFC (21125311 and 91027044) and the National Key Basic Research Foundation of China (2012CB917304) for financial support.

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REFERENCES

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