Water, Properties of

AQ1 Water, Properties of Advanced Article Article Contents Alfons Geiger and Dietmar Paschek, Physikalische Chemie, • Anomalies of Water and Polyamorphism Technische Universität Dortmund, Germany • Hydrogen Bond Network doi: 10.1002/9780470048672.wecb627 • Dynamics of Water Molecules • Hydrophobic Hydration and Interaction • Ion Hydration Water is well known for its unusual properties, which are the so-called • Ionic Influence on Hydration Water and Bulk ‘‘anomalies’’ of the pure liquid, as well as for its special behavior as solvent, Water such as the hydrophobic hydration effects. During the past few years, a • Conclusion wealth of new insights into the origin of these features has been obtained by various experimental approaches and from computer simulation studies. In this review, we discuss points of special interest in the current water research. These points comprise the unusual properties of supercooled water, including the occurrence of liquid–liquid phase transitions, the related structural changes, and the onset of the unusual temperature dependence of the dynamics of the water molecules. The problem of the hydrogen-bond network in the pure liquid, in aqueous mixtures and in solutions, can be approached by percolation theory. The properties of ionic and hydrophobic solvation are discussed in detail. AQ2 It is widely assumed that during the 4 billion years of evolution blocks provide large structural flexibility. The strength as well on our planet, life has adjusted to all properties of water and as the directionality of the H-bonds is intermediate between has taken advantage of any of the numerous unusual features of van der Waals interactions and covalent bonds, which allows this liquid, which has been called “life’s matrix” (1–3). Water easy distortion of the perfect tetrahedral local arrangement and is made of the two most abundant cosmic elements besides the inert helium (4), and it has served as one of the initial a versatile adjustment of the water structure to the changing compounds for the energetically induced reactions to form the thermodynamic conditions or the presence of solutes. AQ3 first organic molecules. This reaction may have happened like in As we largely refer in this short review to simulation results, the Miller-Urey primordial earth atmosphere under the influence the following should be noted beforehand: The first molecular AQ4 of electric discharge (5) or in the porous interior of icy comets dynamics simulation studies of water by Rahman and Stillinger under the influence of cosmic radiation (6). The abundance of (16, 17) were received by the community of water researchers water in our galaxy has been estimated as several ten-thousand with great enthusiasm, as they demonstrated that the structural, earth oceans per sun, and it is distributed on planets, moons, comets, and dust grains mostly in the form of crystalline and dynamic, and thermodynamic properties of this complex liq- amorphous ice. In the past few years, many new aspects of the uid could be reproduced simultaneously to an astonishingly microscopic structure, dynamic behavior, and role of water in high degree by the use of a simple pair interaction potential, biologically relevant molecular processes were obtained from which was made up from Lennard-Jones and Coulombic con- computer simulation studies, which have been performed to tributions. This finding offered an unprecedented opportunity understand various new experimental observations. Therefore, to study structural and dynamic details on the molecular level. in this short review, we will strongly focus on the picture of To improve the reliability of the obtained simulation results water that developed from such computational studies. This review can by no means be complete but lists some points by a better quantitative agreement between simulation model of special interest in the current water research. Because of and real water, many different interaction potentials were de- the importance of water, numerous reviews and monographs on veloped since then. Numerous comparative studies have been different aspects of water can be found (7–13). published. A recent compilation can be found in Reference 18; Water appears in various condensed forms; 15 different crys- other examples, which focus on special properties, are given in talline ice structures are reported, as well as at least three amor- the following sections. Despite these efforts, no current model phous (noncrystalline) ices and a similar number of metastable is fully satisfactory, but the interpretation of simulation results liquid water forms (14). This structural diversity has its origin in the elementary building blocks of water: the hydrogen bonds in comparison with real water can be improved by taking into and the tetrahedral arrangement of H-bonded neighbors [which account the shift of the phase diagram between model liquid is often called the “Walrafen pentagon” (15)]. Both building and real water. WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY  2008, John Wiley & Sons, Inc. 1  Water, Properties of Anomalies of Water and Some indirect experimental evidence exists for the liquid– liquid critical point hypothesis from the changing slope of Polyamorphism the melting curves, which was observed for different ice polymorphs (30, 31). A more direct route to the deeply su- The exceptional rank of water is manifested by its unusual prop- percooled region, by confining water in nanopores to avoid erties compared with most other liquids, the so-called “anoma- crystallization, has been used more recently by experimental- lies.” These anomalies comprise thermodynamic as well as ists. These researchers applied neutron-scattering, dielectric, and structural and dynamic properties, especially their pressure and NMR-relaxation measurements (32–35). These studies focus on temperature dependence. The key to understanding these prop- the dynamic properties and will be discussed later. They indi- erties lies in two competing influences on the local structure: cate a continuous transition from the high to the low-density the attempt to build low-density tetrahedral structures (with low liquid at ambient pressure. The absence of a discontinuity in energy) versus the tendency toward closer packing (with higher this case could be explained by a shift of the second critical entropy) (19). point to positive pressures in the confinement. This finding cor- The density maximum at 4◦ C and the decrease of volume related with simulations, which yield such a shift when water on melting of ice are well-known anomalies. More aspects is confined in a hydrophilic nanopore (36). of the extraordinary behavior of water have been brought Although the presented scenarios are still under discussion, into the focus of many researchers by the seminal articles of the existence of a first-order like transition between metastable Angell on supercooled water (20, 21). In contrast to “ordinary” high- and low-density supercooled water with a second critical liquids, the isothermal compressibility and the heat capacity point at negative pressures in bulk water and positive pres- of water increase drastically during supercooling. This finding sures in confinement is strongly suggested (29). Alternatively, indicates strongly increasing volume and entropy fluctuations singularity-free scenarios are discussed to explain the properties during cooling. A spectacular explanation for this behavior was of supercooled water (24, 29). delivered by a computer simulation study, which gave evidence As indicated above, the study of amorphous solid water in for the existence of a (second) critical point of water buried bulk and in confinement is an important source of informa- in the deeply supercooled liquid region (19, 22) [see also the tion for the understanding of the liquid. In fact, water was reviews by Stanley and Debenedetti (23, 24)]. This second the first liquid to show “polyamorphism”: the mentioned ex- critical point is considered the endpoint of an equilibrium line istence of high density and low-density amorphs. Amorphous between two forms of (metastable) liquid water: a low- and a solid water can be produced experimentally along very differ- high-density liquid. ent routes by vapor deposition, by pressurizing crystalline ice, The two different liquids have their counterparts in the amor- or by fast temperature quench of tiny droplets. Also, differ- phous solid state: the experimentally well-studied high-density ent subsequent annealing procedures have been used. Recently, amorphous (HDA) and low-density amorphous (LDA) ice forms also a very high-density form (VHDA) of amorphous ice was (25). However, it is still unknown exactly how the different observed and shown to be distinct from HDA (37). Neutron amorphous ice forms and supercooled liquid water are con- scattering data revealed that the transformation between HDA nected or where the second critical point is located. A “no man’s and VHDA is related to an increasing population of “inter- stitial” water molecules (38). Simulation studies indicate that land” region largely prohibits direct experimental access to the VHDA (not HDA) should be considered as the amorphous solid low temperature liquid because of the inevitable onset of crys- counterpart to the high-density liquid water phase at ambient tallization (24) in this region. Therefore, computer simulation conditions (39, 40).The question whether the HDA to VHDA studies, in which crystallization does not take place, have been transition is also first-order like (as LDA to HDA) is not yet used extensively to establish the existence of a liquid–liquid resolved (41, 42). The important influence of the preparation transition. The location of the corresponding second critical method has been revealed by several studies. In Koza et al.’s point strongly depends on the interaction potential that was (43) neutron-scattering experiments, HDA and VHDA seem to used in these simulations (26–28). It may be shifted to negative be heterogeneous at the length scale of nanometers, and dif- pressures, which are correlated with the prediction of a van der ferent forms of HDA were obtained depending on the exact Waals-like model developed by Poole et al. (19), in which such preparation process (43). The role of multiple metastability and a shift occurs with decreasing hydrogen bond strength. In such hysteresis has to be studied in more detail. By annealing of HDA a scenario, the experimentally observed diverging fluctuations at normal pressure, Tulk et al. (44) found evidence for the ex- in supercooled water at ambient pressure do not develop by ap- istence of several amorphous ice states. The possible existence proach to the critical point; instead, these fluctuations develop of multiple liquid–liquid phase transitions in liquid water was by the approach to the spinodal line that emerges from the crit- first suggested by Brovchenko and co-workers (27, 45) from AQ5 ical point at negative pressures. This finding could explain the extensive Gibbs-Ensemble Monte Carlo simulations of various early observation of Angell (20, 21), which suggested that all water models. temperature-response functions and temperature coefficients di- verge at the same temperature in ambient pressure supercooled water. The unavoidable crystallization occurs after passing the Hydrogen Bond Network spinodal as it encounters a phase transition to the low-density liquid state, which has a local structure that is very similar to In the perfect crystalline structure of “ordinary” (hexagonal) crystalline ice (29). ice, each water molecule is H-bonded to four tetrahedrally 2 WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY  2008, John Wiley & Sons, Inc.  Water, Properties of arranged neighbors. From the comparison of the enthalpies question of protein hydration is a huge field by its own but of sublimation, melting, and evaporation, it can be concluded beyond the scope of this article. that about 80% of all H-bonds survive the melting process. Despite the wide range of possible definitions of intact versus broken H-bonds (46), it is therefore generally accepted that the Dynamics of Water Molecules water molecules in the liquid form at any instant a random, quasi-infinite, space-filling network (8, 47, 48). This network The molecular motion in water has been studied for decades is subject to constant restructuring [“transient gel” (49)], the with all available modern spectroscopic and scattering methods, lifetime of the individual bonds are in the subpicosecond range including neutron scattering, nuclear magnetic and dielectric (46, 50, 51). Computer simulations revealed that this network relaxation, infrared spectroscopy, and light scattering. Each ap- could be described quantitatively by combinatoric calculations plied method probes different aspects of the motional behavior AQ6 and percolation theory (52).1 on different length and time scales. As NMR furnishes diffusion The physical mechanisms, which are connected with this pri- coefficients and integrals over reorientational correlation func- marily topological phenomenon of the existence of a percolating tions, quasielastic neutron scattering reveals information on the H-bonded network, are still not analyzed in depth. Nonetheless, short-time translational and rotational motion. The results that several observations have been compiled recently that show a were obtained for a wide range of temperature and pressure correlation between the existence of a spanning network and conditions have been interpreted in the frame of translational properties of physical and biological relevance (53–56). These and rotational diffusion models. The temperature dependence of observations concern the occurrence of phase separation in mix- characteristic parameters like reorientation and residence times tures as well as the conformational transition and function of has been discussed in detail (12, 60–62). biomolecules. Computer simulations revealed that the phase That water is so fluent is an apparent contradiction to the separation in a water/tetrahydrofurane mixture is preceded by fact that the space-filling network of hydrogen bonds is made the formation of mesoscopic structures, but “spare” H-bonded up of bonds that have an interaction energy strength well clusters in the organic rich phase, which grow to be space fill- above the thermal energy kBT. This puzzle was resolved by ing at phase separation with a fractal dimension df = 2.5, are showing the importance of network defects: The presence of expected for a percolation cluster in an infinite three dimen- an excess (fifth) neighbor in the first neighbor electron orbital sional system (55, 57). Such percolating networks have also shell allows the intermediate formation of bifurcated H-bonds, AQ8 been detected by neutron-scattering experiments in completely which provides a low-energy barrier path for reorientation and miscible aqueous solutions (58). coupled translational motion (63–65). Consequently, a decrease The space-filling network, which is identified in pure wa- of the local water density (which makes the presence of an ter at ambient conditions, even exists in supercritical water; excess neighbor less probable) decreases the mobility of water the corresponding line of percolation transitions is an ex- molecules. For example, this reaction has been observed by tension of the boiling line (55). The close relation between NMR experiments in the hydration shell of convex hydrophobic demixing phase transition and percolation transition of phys- particles, in which the molecular mobility is decreased (66). ical clusters has also been used in simulations to localize However, it does not decrease to such an extent that one the liquid–liquid transition region in supercooled water. The could speak of “icebergs,” as this is still done occasionally (see AQ7 lowest density amorphous water phase (solid or liquid) has the section entitled “Hydrophobic hydration and interaction”). been characterized by the presence of a percolating network In cold water, the increasing expansion of water reduces the of well-ordered (ice-like tetrahedral), four-coordinated water mobility of the water molecules in addition to the pure thermal molecules, whereas in high-density amorphous water phases, a activation, which leads to a strong non-Arrhenius temperature percolating network of tetrahedrally bonded molecules is miss- dependence of reorientation times, diffusivity, and viscosity (20) ing (54). (see below). The formation of spanning H-bonded water networks on the Implications of the existence of a liquid–liquid phase separa- surface of biomolecules has been connected with the widely tion for the dynamic behavior of water have been discussed accepted view that a certain amount of hydration water is nec- by Angell et al. (67, 68), who postulated a crossover from essary for the dynamics and function of proteins. Its percolative a so-called fragile to a strong glass-forming liquid behav- nature had been suggested first by Careri et al. (59) on the basis ior because of a transition into the region of the low-density of proton conductivity measurements on lysozyme; this hypoth- liquid at deep supercooling. Possible mechanisms were dis- esis was later supported by extensive computer simulations on cussed that dominate the molecular mobility in the different the hydration of proteins like lysozyme and SNase, elastine like temperature ranges (69), which lead to different temperature peptides, and DNA fragments (53). The extremely interesting dependences: At high temperatures, as mentioned above, the switching through bifurcated H-bonds is most effective and is connected with a low activation energy. At lower temperatures 1 A “percolating” network forms an uninterrupted path between opposite beyond the density maximum, a strong non-Arrhenius behavior boundaries of a system. The word “spanning” is used when the system with increasing apparent activation energy is produced by the has no boundary, like the surface of a single sphere. In this case, the degree of connectivity, at which a “spanning” network appears, is development of a more perfect local order, which enforces an detected by the distribution of finite clusters in analogy to a percolation approach to structural arrest of the water molecules in the cages transition. of their neighbors (70). This arrest is then overcome at even WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY  2008, John Wiley & Sons, Inc. 3  Water, Properties of lower temperatures by jump diffusion (71, 72); in other mod- temperatures, theoretical and experimental studies also indicate els by the collective relaxation of the cage of neighbors (73). a slowing down of the translational and reorientational dynamics Finally, in the locally well-ordered, low-density liquid, when of water in the hydration shell of an apolar moiety (66, 81–83) approaching the glass transition, the formation of Frenkel-type (see the section entitled “Water in pores”). Another thermody- defect pairs may enable a diffusion behavior that parallels the namic signature of hydrophobic hydration is the large positive “strong glass former” Arrhenius line of the Angell plot (69). solvation heat capacity. The heat capacity increase is attributed The expected crossover could not be studied experimentally to the temperature-induced mutual interactions among the sol- in pure water because of the onset of crystallization at strong vent molecules in the hydration shell (84). It considered to be supercooling. Recently, the possibility to supercool water to a caused by the progressing disintegration of the hydrogen bond much larger extent than bulk water, when it is confined to small network around the solute with increasing temperature (77, 84). pores, has been exploited (34). From dielectric spectroscopy and Because the solvation of small apolar moieties is accompanied quasielastic neutron-scattering experiments on water confined in by an entropy decrease of the solvent, the formation of con- the nanopores of clays and silica glass, a transition (crossover) tact pairs of apolar particles is a way to reduce this “entropy from a strongly activated non-Arrhenius motional behavior to a penalty.” The tendency to form apolar contact pairs in solution low activation energy Arrhenius line at even lower temperatures is termed “hydrophobic interaction” and essentially controlled has been observed (32, 33). This observation correlates with by the solvent. Because the association of small apolar particles the expected fragile-to-strong transition when crossing from is entropically favorable, a temperature increase leads to more “normal” to low-density water. Using such experiments in an stable apolar contacts. “Hydrophobic interaction” is a classic extended pressure range, the position of the second critical point example of an “entropic force.” could be estimated for the confined water. This fragile-to-strong Contrasting the behavior close to small apolar solutes, water dynamic crossover was also observed for the hydration water of behaves differently at an extended (planar) interface. Here, the biomolecules (proteins and DNA) (74, 75). Most interestingly, thermodynamic features are mostly governed by water’s inter- this crossover occurs at the same temperature as the so called facial tension, which is essentially enthalpic in nature (weak- “protein glass transition,” which suggests that this transition in ening with increasing temperature). Consequently, at some the dynamics of the protein is the result of the approach to length-scale a “crossover” has to occur (85, 86) from an entropy the above-mentioned extension of the liquid–liquid equilibrium to an enthalpy dominated solvation behavior. Recent studies in- line of the solvent (the so-called Widom line of the second dicate that this transition appears at a length-scale significantly critical point of water). It has to be mentioned here that some below 1 nm (87, 88). controversy still surrounds the origin of this abrupt change in the The thermodynamic signatures of small apolar particle hy- temperature dependence of the mobility of the water molecules: dration can be modeled by simple two-state models (89–92) This behavior has also been attributed to the limitation of the that solely focus on water’s hydrogen bonding as supposedly spatial extension of fluctuations in confinements (76). dominating effect. Stronger hydrogen bonds close to an apolar particle are counterbalanced by fewer possible hydrogen bonds. Silverstein et al. (92) consistently related experimental data that described water’s hydrogen bond equilibrium with hydrophobic Hydrophobic Hydration solvation calorimetric data. Their calculations suggest that at and Interaction lower temperatures, the hydrogen bonds are more intact than in the bulk, whereas at high temperatures, hydrogen bonds are The “hydrophobic effect” is manifested thermodynamically by more broken. The model moderately readopts older theories by the low solubility (large positive solvation free energy) that Franks and Evans in their so called “iceberg” model (93), in nonpolar molecules or aggregates experience in water (for more which the hydrophobic particles where thought to be stabiliz- extensive reviews, see References 77–79). The hydrophobic ing structured ice-like entities in water. However, because the effect is of great relevance for a variety of phenomena, which entropy change experienced by a water molecule in a hydropho- include protein folding as well as the structural organization of bic hydration shell is about five times smaller than a crystal-like amphipilic aggregates. The latter are forming micelles of various environment (77), the “iceberg” model too strongly exaggerates topology, as well as lyotropic mesophases and lipid membranes. the degree of ordering that is present in a hydrophobic hydra- Surprisingly, the low solubility of small-sized particles does tion shell (77). Simple two-state models seem to fail in reliably not stem from a weak interaction of particles with their sur- predicting absolute solvation free energies (77) because alter- rounding water environment (77). For example, the heat of ing hydrogen bonding does not provide sufficient information solvation of methane in water at ambient temperature is of simi- to determine the entropic “free volume contribution” (94, 95). lar magnitude as the heat of vaporization of pure liquid methane A conceptually complementary approach to describe hy- (80). The positive solvation free energy of small apolar particles drophobic effects has been introduced by Pratt and colleagues at low temperatures is the consequence of negative solvation (78, 96). Their information theory (IT) model is based on an entropy, which overcompensates for the negative solvation en- application of Widom’s potential distribution theorem (97) com- thalpy. It is widely believed that this “entropy penalty” is caused bined with the perception that the solvation free energy of a by the orientation order introduced to the hydration-shell wa- small, hard sphere, which is essentially governed by the prob- ter molecules as they try to maintain an intact hydrogen bond ability to find an empty sphere, can be expressed as a limit network (77). Parallel to the entropy decrease observed for low of the distribution of water molecules in a cavity of the size 4 WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY  2008, John Wiley & Sons, Inc.  Water, Properties of of the hydrophobic particles. Because the distribution functions Ion Hydration are essentially determined by density fluctuations of water at the molecular scale, the IT model relates the hydration and As already suggested by Max Born in 1920 (114), the large interaction of hydrophobic particles with the temperature de- negative solvation free energies of ions in aqueous solution pendence of waters thermodynamic response functions, such as can be explained by mostly purely electrostatic effects, which expansivity and compressibility. assume water to be represented by a dielectric continuum (115). An instructive, simplified computer model for water is the Small changes of the ion diameter are found to affect the “Mercedes-Benz” (MB) model of Silverstein et al. (98). It has solvation free energies strongly. The measured solvation free been shown to capture qualitatively the anomalous thermody- energies roughly scale with the third power of the ion diameter, namic behavior of water as well as the thermodynamic features as proposed by the Born theory (115). However, a structuring of the hydrophobic effect. The MB-model notably captures the effect on the first hydration shell water is obvious and has been experimentally determined by X-ray and neutron scattering effect of increasing particle size. A hydrophobic particle of techniques (116–119). In case of an anion, the first shell water about twice the size of a water molecule is found to increase the molecules form a hydrogen bond type configuration in which the free energy by a different mechanism, namely by increasingly OH-bond points toward the anion (118), although on average it breaking the hydrogen bonds. Similar to the thermodynamic be- does not point exactly to the center of the ion (117). For the case havior observed for planar interfaces, the mechanism increases of cations, the water molecules are found to be pointing with the enthalpy but has only little effect on the entropy and heat their oxygen toward the ion. The water dipole axis, however, capacity. The simulations indicate that at a large, extended in- seems to exhibit an average tilt of about 30 degrees with ert surface, water is geometrically unable to form its maximal respect to the ion-water-oxygen connecting vector (117, 119). number of hydrogen bonds to other water molecules. Thus, Recent first principles simulations of aqueous salt solutions enthalpically costly “dangling” hydrogen bonds form pointing suggest that this might be an artifact caused by averaging a toward the interface (99, 100). rather broad tilt angle distribution (120). In those simulations, Realistic three-dimensional computer models for water were the dipole vector that points directly toward the ion is the most likely configuration of a broad distribution. Earlier classic proposed already more than 30 years ago (16). However, even MD simulations had revealed a more tilted “lone-pair”-type of relatively simple effective water model potentials based on point ion–water bonding (121), which was possibly a consequence of charges and Lennard-Jones interactions are still very expen- the tetrahedral charge distribution of the employed water model sive computationally. Significant progress with respect to the (17) and is perhaps an artifact. models ability to describe water’s thermodynamic, structural, and dynamic features accurately has been achieved recently (101–103). However, early studies have shown that water mod- Ionic Influence on Hydration Water els essentially capture the effects of hydrophobic hydration and interaction on a near quantitative level (81, 82, 104). Recent and Bulk Water simulations suggest that the exact size of the solvation en- Salts are known to influence several properties of aqueous tropy of hydrophobic particles is related to the ability of the solutions in a systematic way (122, 123). The effect of different water models to account for water’s thermodynamic anoma- anions and cations seems to be ordered in a sequence; this theory lous behavior (105–108). Because the “hydrophobic interaction” was already proposed by Hofmeister in 1888 (124) from a series is inherently a multibody interaction (105), it has been sug- of experiments on the salts ability to precipitate “hen-egg white gested to compute pair- and higher-order contributions from protein.” Numerous other properties of aqueous salt solutions realistic computer simulations. However, currently it is incon- are also found to be systematically salt dependent, such as clusive whether three-body effects are cooperative or anticoop- the surface tension or the surface potential (122). However, erative (109). the exact reason for the observed specific cation and anion An analysis of computer simulations of water at different sequences is still not fully understood (125). Model calculations pressures by Hummer et al. (110) suggested that hydropho- (126), as well as nuclear magnetic relaxation experiments (127), bic contact pairs become increasingly destabilized with in- propose a delicate balance between ion adsorption and exclusion creasing pressure. The proposed scenario could explain the at the solute interface. This balance is tuned by the solvent pressure denaturation of proteins as a swelling in terms of (water) structure modification according to the ion hydration (128, 129) and hence is possibly subject to molecular details. water molecules that enter the hydrophobic core by creating In principle, two different mechanisms have been proposed water-separated hydrophobic contacts. Additional support for on how the ions influence protein stability. Firstly, it has been the validity of Hummer’s IT-model analysis has been achieved suggested that a modification of water’s structure is the origin by pressure-dependent computer simulation studies of isolated of the Hofmeister sequence (130). It has been hypothesized that pairs of hydrophobic particles, as well as rather concentrated some ions “kosmotropes” enhance the structure that surrounds solutions of hydrophobic particles (111, 112). Recently, the the ions, which leads to a strengthening of the hydrophobic ef- pressure-induced swelling of a polymer composed of apolar fect and thereby stabilizes the proteins (131). However, the ions particles at low temperatures can be observed (113). that break the structure that surrounds the ions (“chaotropes”) WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY  2008, John Wiley & Sons, Inc. 5  Water, Properties of have been considered to weaken the hydrophobic effect and water’s unusual properties, or “anomalies,” stem from water’s hence destabilizes the native state of proteins. It has been sug- tendency to form a roughly four-coordinated hydrogen bond gested that the competition between ionic charge and ionic size network. Computer simulations indicate that many effects can determines whether an ion is a chaotrope or a kosmotrope be explained in great detail by simulations based on molecular (126, 132–135). A completely alternative explanation for the models. A pattern reveals that in water. hydrogen bond-based Hofmeister series has been suggested by Timasheff and col- local-order (entropy) and interaction energies have the beneficial leagues (123, 136). They consider the differences in salt–protein tendency to compensate each other, which is important for binding as the main effect for destabilizing proteins. Their many solvation processes and for water structuring and phase analysis of thermodynamic date provided evidence suggesting behavior. The small size of the water molecule and its effective the salts that denature proteins tend to be bound to proteins, hydrogen-bond formation make it a particularly helpful agent in whereas the salts that stabilize proteins tend to be excluded the process of protein folding; it is deemed essential to enable from the protein surface. Using volumetric data of Timasheff protein motions. et al. (123, 136) on the effect of numerous salts on bovine serum albumin, recently Shimizu et al. (137) could show by us- References ing a Kirkwood-Buff theory framework that the water-mediated protein–salt interaction is an important driving force for the 1. Daniel RM, Finney JL, Stoneham M, eds. The molecular basis of protein denaturation. A recent simulation study on a highly ide- life: is life possible without water? In: Philosophical Transactions alized model system by Zangi et al. (138) came to a similar of the Royal Society of London, Volume 359. 2004. The Royal conclusion. 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