Room Temperature Ionic Liquids Meet Biomolecules - American

Research Article pubs.acs.org/journal/ascecg

Room Temperature Ionic Liquids Meet Biomolecules: A Microscopic View of Structure and Dynamics Antonio Benedetto*,†,‡ and Pietro Ballone§ †

School of Physics, University College Dublin, Dublin 4, Ireland Laboratory for Neutron Scattering and Imaging, Paul Scherrer Institut, 5232 Villigen, Switzerland § Istituto Italiano di Tecnologia (IIT), Via Morego 30, I-16163 Genova, Italy ‡

ABSTRACT: Room temperature ionic liquids (RTILs) and biomolecules are both paradigmatic classes of organic molecules, each consisting of a prodigious number of distinct chemical species, organized into large families of homologous compounds. Their combination is set to open new avenues for discoveries and for applications in biochemistry, biomedicine and pharmacology, food science, and nanotechnology. We provide a survey of past and current investigations of the chemical physics properties of systems made of RTILs and biomolecules, focusing on the most microscopic scales of their structure and dynamics. The primary goal of our discussion is to identify the basic principles able to organize and rationalize the vast variety of properties and phenomena displayed by these systems. We consider in turn RTILs combinations with phospholipids, with proteins and peptides, with nucleic acids (mainly DNA) and with carbohydrates from simple sugars to large polysaccharides. These basic components have a clear electrostatic signature, and Coulomb interactions represent the first ordering principle. However, because of size and complexity of both RTILs and biomolecules, dispersion interactions, steric effects, and hydrogen bonding play a secondary but certainly nonnegligible role that is reflected in the sensitive dependence of RTIL/biomolecule properties on the RTIL choice. Our overview of the available results highlights both the need and the difficulty of devising general approaches able to predict properties of at least extended families of RTIL/biomolecules combinations, without having to consider them one by one in turn. KEYWORDS: Neutron scattering, Molecular dynamics, Phospholipids, Proteins, DNA, Carbohydrates, Cellulose, Biocompatible RTILs

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INTRODUCTION Recent years have seen an outpouring of studies and exciting new results on fundamental and applied aspects of room temperature ionic liquids (RTILs, see ref 1). This frantic activity continues unabated, and the vitality of the field as of 2015 is apparent from the number, variety, and interest of talks presented at the COIL-6 conference in Jeju City, South Korea (see the papers in the ACS Sustainable Chemistry & Engineering special issue titled Ionic Liquids at the Interface of Chemistry and Engineering scheduled for February 2016). The spectacular growth of this subject has made it increasingly difficult to think of it as a unique topic. The present contribution is devoted to one specific aspect, concerning the chemical physics of systems made of RTILs and biomolecules. This subject is still a small fraction of the whole RTIL research field but has, however, a bright future, partly because it concerns the toxicology, health, and environmental safety of RTILs,2−6 but especially because RTIL/biomolecule systems have a major potential for applications in biochemistry, biomedicine, food science, conversion of biomass into liquid fuel, and nanotechnology.7,8 Because of our interests and professional background, and also for the sake of definiteness, we stay away from the most genuinely biological issues, whose review, moreover, would take © XXXX American Chemical Society

much more space than available. However, since the primary motivations underlying this research field are applied, we will briefly touch upon biochemistry and pharmaceutical aspects9−15 whenever required by our discussion. To ease the systematic exposition of our subject, we limit the range of biomolecules to four broad classes, i.e., (i) phospholipids, (ii) DNA and RNA nucleic acids, (iii) proteins and peptides, and (iv) simple sugars, carbohydrate oligomers (complex sugars, cyclo-dextrins), and polymers (cellulose, chitin, etc.). We do not feel it is necessary to define or delimit the RTIL family in a contribution intended for a professional science journal’s special issue of a major international conference on these compounds. We provide, however, a summary in graphics (see Figure 1) and in table form (see Table I) of the ionic species that appear more often in our discussion. Special Issue: Ionic Liquids at the Interface of Chemistry and Engineering Received: October 29, 2015 Revised: December 4, 2015

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DOI: 10.1021/acssuschemeng.5b01385 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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occurs via a single ionic species. This is no longer the case with the large and complex ions found in RTILs, since in this case, polarizability, dispersion forces, steric interactions, and hydrogen bonding contribute significantly to the system free energy. These effects, usually still smaller than pure charge effects, underlie the rich variety of behaviors and properties already observed in biomolecule/RTIL combinations. The vast number of RTIL ions and of biomolecules makes it imperative to find some ordering in the huge variety of these specific effects, identifying basic interactions that can be used to rationalize, classify, and eventually predict the properties of the systems discussed in our paper. Needless to say, we are very far from this goal. Nevertheless, we can be confident that even in the near future we will witness a spectacular progress toward this aim, since powerful experimental and computational methods are available to probe the microscopic structure and dynamics of biomolecules interaction with RTIL ions. In what follows, we will consider systems made of just two components, i.e., the RTIL and the biomolecular species, or three component systems, with water solvating the two other compounds. In a few cases, the two qualities of being an RTIL and of being a biomolecular species are combined in the same compound.16−20 The interest of RTILs as solvents in extraction and purification has driven a fairly large number of studies on solubility and partitioning of solutes between competing solvents. These studies and, in general, the determination of the phase diagram of two- and three-component RTIL/ biomolecule systems are carried out by macroscopic means, using thermodynamics, visual inspection, and sometimes optical microscopy. A special role is played by differential scanning calorimetry that provides information not only on solubility, but also on a variety of thermodynamic and/or structural transformations that may occur in these systems. Our interest, however, is directed primarily toward the molecular interactions and mechanisms underlying these and even more complex phenomena. For this reason, we turn to a more microscopic analysis down to the atomistic structure and dynamics that can be determined by X-ray and neutron scattering and diffraction, NMR, and vibrational spectroscopy, up to scales (5−10 nm) that can be investigated by circular dichroism (CD), luminescence spectroscopy, and near field imaging and microscopy such as AFM. Increasingly, these systems and microscopic properties are investigated by computational means, especially by classical molecular dynamics21 based on empirical force fields,22−24 with a small but conceptually important role for ab initio approaches.25 Force field studies, in particular, profit from the success of general particles-andbonds models for biomolecules22,23 and from the reliability and accuracy of RTIL-specific force fields.24 In our discussion, we will encounter many further examples of the power of these models and of their mutual compatibility, as well as of the general success of simulation approaches for these systems. Stepping slightly beyond our self-imposed boundaries, we will briefly mention a recent extension to the RTIL concept, represented by the so-called deep eutectic solvents (DES),26−28 consisting of room temperature ionic fluids made by dissolving a solid organic salt into a non-ionic organic solvent at the concentration that minimizes the melting temperature of the resulting mixture. DES might provide milder more biocompatible and also cheaper solvents than traditional RTILs, particularly suitable for combinations with biomolecules. A more restricted review of current research on RTILs and biomolecules has been published in ref 29. In that and in the

Figure 1. Schematic structures of RTIL cations: (a) cations of the imidazolium [Cnmim]+ family; n = 1:[mmim]+; n = 2: [emim]+; n = 4: [bmim]+; n = 8: [omim]+ and (b) other cation prototypes.

Table I. Representative Anions in RTILs and Their Common Abbreviationsa

a

formula

name

abbreviation

CH3COO− CH3CH2OSO−3 CF3SO−3 N(CF3SO2)−2

acetate ethylsulfate trifluoromethanesulfonate bis(trifluorometahnesulfonyl)imide

[Ac]− [EtOSO3]− [TfO]− [Tf2N]

The simplest cases such as [Cl]−, [Br]−, [I]−, and [PF6]− are omitted.

Most biomolecules have a clear electrostatic signature. Phospholipids can be ionic (usually anionic), and even zwitterionic species carry a large dipole; nucleic acids are anionic, with a fairly large charge per unit length along their chain; proteins are usually charged, but their total Z varies according to chemical (pH) and physical (temperature, pressure) conditions and can change sign across their point of zero charge; carbohydrates arguably are the least Coulombic of all systems in our discussion, but their numerous OH groups still carry an electrostatic dipole. As a consequence, the interaction of biomolecules with simple electrolytes often B


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ACS Sustainable Chemistry & Engineering present review, the account of contributions available in the literature was never meant and could not be exhaustive and is instead driven by examples. We apologize to the authors of the many papers that we neglected for reasons of space or for the limits of our knowledge.

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IONIC LIQUIDS AND PHOSPHOLIPID BILAYERS Phospholipid molecules in water give origin to a wide variety of structures, ranging in size from nanometric and micrometric micelles and vesicles up to extended (2D) bilayers and 3D structures made by stacking nearly parallel bilayers separated by a thin hydration layer. The interest in lipid bilayers, of course, relies on their being idealized but nevertheless relevant models of biomembranes. The watery environment in which biomembranes reside and operate, however, contains also a variety of ions, whose chemical identity, concentration, and spatial distribution are crucial for the fine-tuning and control of biomembrane functions. The effect of simple ions such as Na+, K+, Cl−, etc. on a model phospholipid bilayer such as saturated DMPC or singly unsaturated POPC, POPE, etc. has been studied extensively with experimental and computational methods30−32 and also with empirical modeling (Hofmeister series, see the Ionic Liquids and Peptides/Proteins section).33 It is only natural, therefore, to turn our attention to organic ionic salts, whose complex structure and larger size provide many more handles to tune their interaction with lipid molecules and with their self-organized structures such as phospholipid bilayers. Early Experiments and Molecular Dynamics Simulations. The interaction of RTIL ions with prototypical phospholipid bilayers in water has been one of the first instances of RTIL/biomolecules investigations.34−36 The RTIL species considered in these early studies included one pyrrolidinium and a few [Cnmim]+ compounds with n up to 8. In all cases, measurements revealed the alteration and eventual disruption of the bilayers. Along the [Cnmim]+ sequence, the experimental data document the progression of damage from the formation of localized holes at low concentration and short Cn tails to the massive permeabilisation of the bilayer at high concentration and long Cn tails. The role of the cation tail length n highlights their direct involvement in the disruption of the bilayer, hinting at the incorporation of RTIL cations into the lipid phase. Moreover, since the tail is the neutral moiety of [Cnmim]+, the dependence of the bilayer fate on the tail length points to dispersion forces as being an important factor (together with Coulomb forces, common to all cations) for the affinity of [Cnmim]+ for phospholipid molecules. The dependence of the bilayer damage on the anion is somewhat weaker and less well-defined, but again it points to the important role of dispersion interactions, complementing Coulomb and steric forces in determining the structure and stability of phospholipid bilayers in RTIL/water solutions. These observations motivated a number of computer simulations,37−40 reproducing the absorption of cations by phospholipid bilayers and complementing the general picture proposed by experiments with a wealth of microscopic details on the structure and dynamics of ternary water/RTIL/ phospholipid systems (see Figure 2). Animations from MD trajectories,37,40 for instance, show that [C4mim]+ cations enter POPC bilayers within a few nanoseconds of equilibration. Absorption of [C4mim]+ takes place tail first, where tail is again the neutral C4 moiety of [C4mim]+. As expected, these cations solvate their tail into the neutral hydrocarbon (bi)-layer of the

Figure 2. Snapshot from the MD simulations of ref 40. POPC domains in gray, water layers in red, [bmim]+ in blue, and [PF6]− in green. Inset (a): Representative configuration of POPC and [bmim]+ from the [bmim][Cl] MD simulations. Inset (b): water density profile in the POPC sample with pure water (back curve); same profile upon addition of [bmim][Cl] in solution (blue curve). The difference highlighted in red points to a water excess in the POPC doped with [bmim]+.

lipid phase and position their ionic head close to the polar head of (zwitterionic) phospholipids (see inset (a), Figure 2). According to ref 40, the absorption of cations into the bilayer drives the incorporation of a few additional water molecules in the vicinity of the lipids’ polar head, screening the charge of the cations (see inset (b), Figure 2). The role of the anions depends on their water affinity. Highly soluble species such as [Cl]− remain in the water interlayer and limit the penetration of cations into POPC. Anions whose water solubility is low, such as [PF6]− or [NTf2]−, tend to segregate at the water/lipid interface and contribute to the structural disorganization of the phospholipid bilayer. According to simulation, the incorporation of cations into the bilayer causes a slight expansion of the cross area40 and a systematic thinning of about 0.5 Å Simulation results also show that the presence of RTIL ions in solution affects the diffusion constant of both lipids and water. Studies of stacks of POPC bilayers separated by nanometric (δ ∼ 2 nm) water films40 show that the diffusion coefficient of water decreases by ∼25% upon the addition of [bmim][Cl] or [bmim][PF6] ([bmim]+ ≡ [C4mim]+) to the water solvent at 0.5 M concentration. The variation of the diffusion coefficient of lipids is not systematic but depends on the lipid and on the RTIL choice. However, the determination of the modest variation in Dlip, which itself is of the order of 10−8 cm2, is challenging and still affected by important statistical error bars. The slow down of water diffusion might be due to the enhanced stability of hydrogen bonding at the water/lipid interface. On the other hand, the RTIL addition decreases the bending rigidity of the bilayer, hinting to one of the mechanisms of destabilization of the lipid structure. Free energy profiles for the cation insertion into zwitterionic phospholipid bilayers have been determined in refs 41 and 38. Although valuable, these results are still as good as the force field model used to carry out the MD simulation, and the only way to validate them has to rely on the comparison with experiments able to provide microscopic information on the system structure and dynamics. C


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ACS Sustainable Chemistry & Engineering Neutron Reflectometry Measurements. Arguably, the most structure sensitive measurements on these systems are represented by recent neutron reflectometry studies42 of phospholipid bilayers deposited on a planar oxidized silicon surface. With respect to other structural-sensitive methods such as X-ray reflectometry or diffraction, neutron scattering has the advantage of applying only a weak perturbation to the system, covering a wide area, aiming at the determination of the density profile of all species in the direction z perpendicular to the interface reference plane (see Figure 3). Moreover, isotopic

satisfy competing requirements. In particular, increasing the number of components makes the fit less and less well conditioned, raising the risk of spurious results. The stability of the fit is enhanced by a large difference in the scattering length density of each component, and in this respect, isotopic substitution plays a crucial and positive role. The details of the method (composition space approach) used to fit the raw data in ref 42 are explained in ref 43. In ref 42, the system is represented as the superposition of the silica surface, water buffer, lower and upper phospholipid leaflet, and bulk hydration water. Each lipid leaflet could be split into its tail and head components. Moreover, RTIL solution samples included the density profile of ions as an additional variable in the fit. Deuteration concerned both the phospholipid (tails and/or heads) as well as the hydration water. The output of the experiment is the density profile of all species along the direction z perpendicular to the surface. The results, shown in Figure 3, could be summarized as follows: (a) the bilayer is still homogeneous in 2D at the RTIL concentrations (∼0.5M) of the experiment; (b) cations enter the bilayer, and find their equilibrium location at the junction between the phosphonium polar head and neutral hydrocarbon tail of phospholipid molecules; (c) the bilayer thickness shrinks slightly (∼1 Å), in analogy with other measurements on amphiphilic layered systems,44,45 and in qualitative agreement with the results of simulations (see Figure 2). Given the lower overall resolution, the determination of a 1 Å variation of the bilayer thickness is a remarkable feat, made possible by the compensation of errors resulting from the simultaneous fit of all reflectometry data, concerning both neat and RTIL-doped samples. Together with ongoing measurements on the dynamics by quasi-elastic neutron scattering,46 the results of this structural study largely agree with the findings of molecular dynamics simulations for the same and similar systems. This agreement opens the way to a wide range exploration of lipid/RTIL systems by computational means. The preferential association of lipid polar heads with RTIL cations is indirectly confirmed by a remarkable application in extraction and purification techniques.47 The selective solvation properties of hydroxyl- and carboxyl-functionalized RTIL cations allow the separation of even homologue zwitterionic phospholipid species out of homogeneous mixtures, exploiting multiple hydrogen bonds between phospholipids and cations to achieve molecular recognition. The all important recovery of the RTIL solvent after extraction can be achieved by electrodialysis, exploiting the charge of the RTIL ions. Selectivity of solvation properties can be further enhanced by the propensity of RTILs to form mesophases, alternating nanometric domains of neutral and charged cationic moieties.48−52 In the context of RTIL/lipid interactions, this subtle effect has been used to solvate cholesterol into longchain carboxylate ILs.53 Other Experimental Approaches. A broader picture of structures and phases is provided by two recent studies of lipid self-assembly in pure RTILs and in RTIL/water solutions. Microscopic structural information is made available by their usage of high-resolution solution X-scattering in the small(SAXS) and wide-angle (WAXS) X-ray scattering flavours. Both charged anionic (DLPS54) and zwitterionic (DLPC55) phospholipids have been considered, while RTILs were represented by the single choice of 1-ethyl-3-methyl

Figure 3. Neutron reflectivity as a function of the momentum transfer Qz measured on DMPC bilayer before and during the interaction with [bmim][Cl] from ref 42. Data for three different H/D solvent contrasts were collected for each of the two (neat and interaction) stages. The solid lines are the best fit to the data. Inset: Volume occupancy profiles as a function of height z from the surface. RTIL absorption accounts for 10% of the bilayer volume.

substitution (deuteration) can be used to alter the scattering properties of selected chemical species, providing additional information on the molecular distribution across the system. In the measurements of ref 42, the bilayer is separated from silica by a nanometric water film, and the system is hydrated by a macroscopic water environment. This consists of pure water, or of a water solution of electrolytes, and of RTIL ions in particular. Bilayers made of POPC and DMPC have been considered, whose hydrocarbon tail may contain natural hydrogen or it might be deuterated. The RTIL consisted of [bmim][Cl], but also of [Chol][Cl], in which the organic cation is represented by a biocompatible species that is naturally present in cells. The neutron beam is directed toward the planar surface at a given incidence angle, and the reflection coefficient is measured at the angle of specular reflection. An example of the raw results is shown in Figure 3. As expected, reflectivity is highest at grazing incidence, and the reflection coefficient 9 decreases with increasing incidence angle. Models and parameters are available to predict the reflectivity coefficient 9 as a function of θ of homogeneous films of given chemical and isotopic composition, and matching the predicted with the measured 9(θ ) is a way to reconstruct the profile of the different components. The method relies on the assumption that the distribution of each component is uniform along the surface plane, and the system is made by the stacking of a given number of distinct layers. The choice of the number and quality of the layers introduced to fit the raw data has to D


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ACS Sustainable Chemistry & Engineering imidazolium ethyl sulfate ([emim][EtOSO3]).55 In both cases, the primary measured quantity is the repetition length in 3D stacks of bilayers. The phase diagram is drawn as a function of the RTIL concentration and of the osmotic pressure that is applied by the addition of a large polymeric species (PEG) that floats in the hydration reservoir but cannot enter the lipid stack because of its size. The application of the osmotic pressure decreases the repetition length between bilayers and confines the system into a volume lower than the P = 0 equilibrium value. In the zwitterionic case, with increasing concentration, the results display a variety of trends and sudden changes of phases. In very dilute ( HPO24− > CH3COO− > Cl− > NO−3 > Br− > ClO−3 > I− > ClO−4 > SCN−

where the salting-out power is highest on the left and decreases in moving toward the right of the series. The generality of the Hofmeister series would suggest that it reflects the interaction of the salt with water, but recent studies contradict this interpretation,98,99 attributing the predicting power of the series to specific salt/solute and salt/water interactions.100 An extended version that includes anions and cations from RTILs reads:72,97 SO24− > [dhp]− > [Ac]− || [EtOSO3]− > [BF4 ]− > [TfO]− > I− > [SCN]− ∼ [dca]− > >[Tf 2N]−

and K+ > Na + > [Me4N]+ || Li+ > [chol]+ > [Et4N]+ ∼ [C2mim]+ ∼ [gua]+ > [C4 mpyr]+ > [C4mim]+

where the || sign marks the change from salting-out to salting-in effects. G


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computational approaches and facilities, and therefore, MD can still miss important results that would otherwise be available with larger scale/longer time simulations. In addition to these systematic studies, the available literature offers a number of detailed contributions. These include, for instance, the analysis of the changes in the structure of lysozyme due to the addition of [pmim][Br] (fluorescence (FCS and MD), see ref 130) or [bmim][TfO] (ref 131, investigated by 2D Fourier transform infrared spectroscopy (see Figure 4c). The experimental data show that [pmim][Br] decreases the apparent size of the protein and increases the rate of its dynamics. At 1.5 M [pmim][Br] concentration, the effect is surprisingly large; the hydrodynamic radius decreases from 18 to11 Å, while its conformational relaxation time decreases by one full order of magnitude from 65 to 5 μs. Molecular dynamics suggest that these changes are due to the replacement of the lysozyme hydration water by RTIL cations. The same [pmim][Br], however, unfolds another globular protein, i.e., human serum albumin (HSA), increasing its hydrodynamic radius, slowing down diffusion and conformation dynamics, as monitored by fluorescence correlation spectroscopy.132,133 The effect of [bmim][Cl] on the structure of a green fluorescent protein has been investigated by UV and visible spectroscopy and small angle neutron scattering (SANS), revealing a mild destabilizing effect of [bmim][Cl] both at ambient and at higher temperature.134 The message collectively provided by all these studies of protein−RTIL interactions can be summarized as follows: (i) the results of computations and experiments are in fair agreement with each other;128 (ii) because of charge and dispersion forces, cations tend to be more closely coordinated to proteins than anions; (iii) the relative role of the anions and cations, however, depends on the protein charge, that in turn changes with (at least) the pH of the solution/environment; (iv) the ion most closely coordinated to the protein body interact by a combination of Coulomb and short-range forces (dispersion H-bonding, steric interactions) and thus is responsible for specific effects arising from the protein−RTIL interaction; (v) the ion of opposite charge, instead, interacts with the protein mainly by Coulomb forces. In many respects, also taking into account the variety of systems and the diversity of results, the most positive side of the message is that the machinery needed to simulate RTIL/ protein systems is in place, and in principle, we could investigate the mutual effect of interacting proteins and RTILs up to fairly large size and complexity. However, investigating protein and RTIL systems one by one is certainly inconvenient and time consuming to say the least, and therefore, the search is on for a fairly general picture able to cover broad classes of these two families of compounds. Effect of RTILs on Amyloid Fibers Formation and Stability. The effect of RTIL ions on the propensity of proteins to aggregate into amyloids could be seen as part of the general discussion of stabilization/destabilization of proteins and peptides by organic ionic liquids. However, since amyloids represent an important and very peculiar phase of proteins, and even more, since they are related to crucial medical issues (Alzheimer, Parkinson’s, and Creutzfeld−Jacob disease,135 among others), we summarize the results on amyloids in this paragraph. The subject might have been initiated by a series of papers by Byrne and Angell136−138 reporting that RTIL ions may have both stabilizing and destabilizing effects on fibrillation, according to the protein and RTIL choice, but

energy landscape. The results show that the peptide unfolds, and the unfolded state absorbs a much higher concentration of acetate anions than the folded state, possibly pointing to the driving force for denaturation. A population of cations of fixed size is tightly bound to the peptide backbone and provide the substrate for the acetate absorption. Miscellaneous Studies of Proteins and RTILs. Beyond thermodynamics and solubility aspects, little detailed information is available on the mutual conformation of RTIL ions and proteins that could shed light on the basic principles of ion/ protein interactions. Arguably, the most important aspect could be the absorption of RTIL ions at the protein/water interface that changes the charge at the protein surface83−85 but also alters the hydrophobic/hydrophilic pattern of domains that greatly affects the functioning of proteins. In simple electrolyte solutions, the protein charge is determined by the equilibrium protonation of hydroxyl- and amino-groups and depends sensitively on the pH of the environment, whose variations can even reverse the sign of the overall charge. In RTIL water solutions, dispersion energy, ion size, and additional H-bonding sites come into play. These aspects have been analyzed by NMR in refs 122 and 123, fluorescence spectroscopy in refs 83−85, and in a series of papers based on differential scanning calorimetry.72,124 In at least one case,77 the combination of different spectroscopies (fluorescence, DC, dynamic light scattering) has shown an accumulation of 1-allyl-3-methylimidazolium cations at the surface of hemoglobin in RTIL/ water solution. As pointed out by the authors, however, the result might depend on the pH and thus on the protein charge. Despite the interest of these studies, it is still difficult to identify a unique and coherent picture for the interpretation (and far less prediction) of the effect of RTIL addition on the properties of proteins in water solution. In principle, computational methods could play a major role in investigating the microscopic details of the RTIL effect on the structure and dynamics at the protein/water interface. Studies of this subject are reported at an accelerating rate, but the sheer size of the task implies that this exploration is still in its preliminary stages. A representative example (chosen among several others) of computational approach to these problems is provided by ref 125, reporting MD results for thermodynamic and structural properties of a lipase [Candida Antarctica lipase B] protein in eight different RTILs based on AMBER and CLaP force fields (see Figure 4a). A second example,126 based on a similar model (CHARMM), concerns the investigation of the structure and dynamics of ubiquitin in [emim][CF3SO3]−/ water solutions, and a third example could be the analysis of stability of the three-helix bundle of domain B, protein A from Staphylococcus aureus in [bmim][Cl]/water solution.127 Most of the conclusions from these studies fully conform to expectations, including the dominance of Coulomb forces, with a nonnegligible secondary role for dispersion forces, and the enthalpy required to solvate the protein in (concentrated) RTIL solutions is large and repulsive, meaning that solubility is low. More interestingly, simulation results point to the depletion of water at the protein/solvent interface as the primary reason for stabilization by RTIL ions,126−129 at least in the case of imidazolium-based RTILs. Unfortunately, full and direct confirmation of this picture by experiments is still elusive, despite encouraging indirect support.77,130 It might be worth pointing out, however, that the time required for large scale changes in the protein structure (such as folding of transitions in the quaternary structure) is still long for present days H


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Figure 5. BLB crystallization in the absence (a) of IL and in the presence of 0.2 M (b) or 0.4 M (c) [bmim][MDEGSO4] from ref 151.

copy.145 The computational counterpart to this study is represented by ref 56. As mentioned in the first few paragraph of this section, proteins and peptides often combine with other molecules of biological interest to give origin to new species of enhanced properties. An obvious case is provided by glyco-proteins,59,146 but we want to mention here peptidoglycans, consisting of a gel made of peptides and carbohydrates, and representing an essential component of the bacterial wall. Among RTILs, compounds based on phosphonium dication display a remarkable bactericidal activity.147 Tracing this effect to the ability of phosphonium dications to cross or disrupt the peptidogly can mesh would represent a major discovery, pointing to new families of antibiotics. Models and simulations of pure liquid phases of RTIL dications are available,148 but their interaction with lipids and peptidoglycans has not been investigated yet. RTILs have been used as additives to fold149,150 and also to crystallize proteins (see Figure 5).151−153 Protein crystallization, however, is an art as much as a science, and not surprisingly, the positive effect of RTILs on the crystal nucleation rate and on the quality of the resulting crystals is not general but extends only to selected proteins.154 In many cases, the separation (segregation) of water and RTILs in the last phases of crystallization is desirable, leaving behind the pure protein crystal. The co-crystallization of proteins and RTILs, however, could be equally interesting since high resolution structures of mixed crystals could greatly enhance our knowledge of protein−RTIL favored geometries. A few such structures have been determined,155,156 but many more are needed for an extensive, perhaps bioinformatics-based, determination of RTIL−protein interactions.

dependent also on a number of parameters such as pH, temperature, etc. In favorable cases, RTILs were shown to be able to dissolve amyloids that otherwise are known to be remarkable stable and even to restore the enzymatic activity of the newly solvated proteins.139 A number of studies followed these first ones.102,140−142 The last paper,142 in particular, provides a somewhat indirect but remarkably rich picture of the RTIL role in the structural transformation of lysozyme joining the native and fibril state. Such a detailed view has been obtained by the careful analysis of Raman spectroscopy data targeting aromatic residues in lysozyme. The general picture is that RTILs can greatly affect fibrillation (both ways) and could also be used to drive the formation of intermediate, i.e., nonequilibrium, conformers.102 The structure of several RTILs is known to present heterogeneous features on the mesoscopic (few nm) scale48−52 due to the tendency of charged and neutral moieties of cations to segregate into disjoint domains. The variety of sizes and topologies of these mesophases greatly increases if water is included into the picture. Proteins can be selectively absorbed into one of these mesophases, affecting their structure, stability, and enzymatic activity. At least in one case, this effect seems to determine, or more precisely, prevent fibrillation of lysozyme in [bmim][NO3]/water solutions.143 In many respects, the effect of mesophases is similar to that of the inhomogeneous and anisotropic biphasic environments used to separate proteins and to carry out enzymatic reactions. Further Considerations and Outlook. We now turn to a few loose ends left out of our discussion on proteins and RTILs. Membrane proteins represent an important subclass of these biomolecules whose structure is optimized for operating not only in water, but also in the lipid phase in which they are partly embedded. For this reason, they might be easier to adapt to organic and usually amphiphilic partners such as RTILs. Their role as pores and especially channels might find applications in electrochemistry 144 and sensing. 82 The comprehensive study of one such membrane protein is exemplified by the experimental analysis of gramicidin,56,145 which is a peptide complex forming transmembrane ion channels. From the pharmaceutical point of view it is of interest for its bactericidal activity, while from the biophysics point of view, the interest is due to the simplicity and small size of the channel, coupled to a highly selective permeability to monovalent cations. The effect of BMOP (N-butyl-N-methyl-2oxopyrrolidinium bromide) on the permeability has been studied by circular dichroism, steady state and time-resolved fluorescence, dynamic surface tension, and near-field micros-

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IONIC LIQUIDS AND NUCLEIC ACIDS Nucleic acids such as DNA and RNA are anionic polyelectrolytes of fairly high linear charge, whose stability and normal operation require their detailed screening by counterions. For the sake of simplicity, we shall focus our discussion primarily on DNA, partly because several results and conclusions apply equally well to RNA, partly because RNA is intrinsically less stable than DNA, and also because the literature on RTILs and DNA is far more abundant than its RNA counterpart. At ambient conditions and in physiological solution, the usual structure of DNA is the so-called B-helical (double helix), whose stability, however, is restricted to fairly low (i.e., ambient) temperature and whose lifetime is limited (up to about 1 month) by hydrolytic attack causing deamination and depurination of its base pairs. I


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Figure 6. Water vs [bmim]+ cations competition in hydration/solvation of the minor groove of DNA: (a) water only and (b) 5 wt % and (c) 80 wt % IL solutions. Figure from ref 164.

Figure 7. (a) Choline ions solvating the minor groove of A-T base pairs duplex of DNA, together with (b) atomic-scale representation of the DNACho+ bounds. Color code in (b): phosphorus, oxygen, nitrogen, and hydrogen atoms are in gold, red, blue, and white, respectively. The carbons of choline ions are in yellow; the carbons of DNA are in green. Hydrogen bonds are shown as yellow dotted lines. Figures taken from ref 173.

In the case of DNA interacting with simple inorganic salts in water solution, Coulomb forces again dominate the picture.157 The anionic charge of the phosphate groups attract the electrolyte cations that typically bind to the major or minor groove of DNA, according to their valence, size, ambient pH, etc., and also depending on the DNA sequence. Highly charged cationic species can drive the system to Manning−Oosawa condensation158−161 that represents an intriguing collective behavior of polyelectrolytes. At variance from the simple salt case, the interaction of DNA and RNA with RTIL ions is crucially complemented by dispersion forces, hydrogen bonding, and size (steric) effects, giving origin to a variety of specific (i.e., cation-sensitive) effects. The combination of several of these parameters might be summarized by the interplay of hydrophilic and hydrophobic conditions at the interface between DNA and water (see Figure 6). Enhanced DNA Stability in Selected RTILs. The first clear indication that something peculiar takes place between nucleic acids and RTIL ions has been provided by the

observation of unusual stability of DNA stored at room temperature in RTIL/water solutions.162 In this context, stability concerns both the conservation of the double helix structure, as well as the chemical integrity of DNA. Solvation of DNA into hydrated choline-based RTILs increases the DNA lifetime by 1 order of magnitude and extends its stability range up to temperatures of the order of 90 °C. Because of the predominantly anionic character of DNA, the closest approaching ions are cations that also in the RTIL case bind at the grooves in the DNA double-helix structure. In the RTIL case, the choice between major and minor groove is affected by dispersion forces and by hydrogen bonding, in addition to size. The cation valence is no longer a relevant parameter since in the RTIL case their charge is almost invariably +e. Both in the major and in the minor groove, the effect of the organic cations is to expel (part of the) water from immediate contact with DNA, increasing the thermal stability of DNA and also screening it from hydrolytic attack. J


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microscopy, tunnelling electron microscopy). The results show that indeed Gua-IL has a remarkable ability for DNA compaction, reaching a state that seems to be the analogue of a Manning−Oosawa condensate. Since this process requires high-Z electrolytes (Z > 3), this observation is seen as evidence that cations form highly charged micelles prior to compaction. A further example of DNA packaging using [bmim][PF6] is reported in ref 180. Despite the usage of an impressive battery of experimental methods, including 31P NMR, Fourier transform IR, and circular dichroism spectroscopy, the information on the microscopic structure is only circumstantial, and no simple model for the system conformation is proposed. It is not possible, in particular, to conclude whether compaction results from a bona fide Manning transition or is a lesser form of local neutralization and condensation. Given the interest of the proposed applications to gene transformation, the system and the self-assembly process described in ref 180 are prime candidates for computational analysis by MD simulations. Miscellaneous Studies. While the B-Form duplex (double helix) represents the usual and arguably most relevant state of DNA at ambient conditions, several other (∼10) configurations are known, including triplex (see Figure 8), quadruplex, and i-

Exemplary from this point of view is the study of the geometry and binding energy of morpholinium on DNA, using circular dichroism, fluorescence correlation spectroscopy, and molecular docking approaches.163 Stability is quantified by measuring the melting temperature of the DNA/RTIL complex. The results show that in this case the morpholinium cation binds to the minor groove of DNA and points to the replacement of water by cations as a major mechanism for the DNA stabilization with respect to hydrolysis. A closer look to the structure is provided by molecular dynamics investigations, such as those reported in refs 164 and 165, whose result support and expand those of the experimental studies, emphasizing the role of dehydration in the long term/high temperature stabilization of DNA (see Figure 6). In extreme cases, dehydration affected even the inner layer of tightly bound water molecules that represent the so-called spine of hydration of the grooves.164 It should not be neglected that in some cases the protective effect might also be due to the denaturation by RTILs of enzymes that promote the chemical attach to nucleic acids, such as nuclease.162,166 A second experimental observation emphasizes the role of cation absorption at grooves. It has been known for a long time that in physiological buffered solutions G-C base pairs enjoy a slight stability advantage with respect to A-T base pairs,167 reflected in the systematic increase of the melting temperature of DNA with increasing GC fractional content. A similar study of DNA melting shows that the relative stability of GC and AT pairs is reversed in solutions containing cations such as [TMA]+168 or choline,169 instead of simpler ions such as Na+ or K+, opening new opportunities in the manipulation of nucleic acids. Also in this case, the cation-specific absorption in the minor or major grooves of DNA explains the observation, as shown by structural sensitive experiments170,171 and by detailed modeling studies (see Figure 7).172,173 The role of anions is left unspecified by most of the studies published until now, although thermodynamic properties such as the free energy of binding of RTIL ion pairs to DNA are known to depend on the anion choice.164 Experimental data for this quantities have been obtained by fluorescence measurements174 and by electrochemical approaches.175 DNA Condensation and Compaction in RTILs. Storage and long-term stabilization of DNA may require its folding into a compact, possibly ordered, phase. In eukaryotic cells, this is achieved through the formation of chromatin. This process requires an adequate supply of counterions, represented by cationic proteins and peptides. DNA compaction might find many applications also in nanotechnology, and in the lab, this was achieved176 by addition of multivalent counters ions such as polyamines (spermine, spermidine), dendrimers, etc. The high charge of these species is a necessary condition to drive the system toward a state resembling the Manning condensate. RTILs could play an important role in DNA compaction (also known as DNA packaging); therefore, this process has already been repeatedly investigated (see, for instance, ref 177). The low specific charge of RTIL cations (Z = 1 in most cases) might seem to prevent their Manning condensation, but this limitation may be circumvented by the formation of polyvalent cationic micelles, for which experimental evidence might already be available (see below).178,179 More precisely, in ref 177, the DNA compaction ability of Gua-IL has been analyzed using several spectroscopies (UV, visible,fluorescence, circular dichroism, dynamic lights scattering, scanning electron

Figure 8. (a) Cations distributions around DNA triplex, together with (b) a schematic view of the DNA triplex structure from ref 183. Color code: cyan, green, and pink balls represent the first, second, and third strands, respectively. Yellow particles, carbon atoms of [Chol]+; orange, carbon atoms of [TMA]+; red, oxygen atoms of [Chol]+; gold, Na+ ions. White particles, hydrogen atoms of [Chol]+ or [TMA]+. All views are of the major groove side of the DNA triplex. Cation concentrations of 1.7 M.

motifs. All these forms play rather restricted roles in biosystems but might find important applications in catalysis, sensing, and in nanotechnology.166 Their formation depends on thermodynamic and kinetic conditions, and it might be driven and controlled by suitable counterions. Once again, RTILs have been proposed and already used in experiments181,182 as tunable ingredients to achieve these goals, while MD simulations in ref 183 provide a remarkably detailed and informative view of the structural and thermodynamic factors that determine the effect of cations (Na+, [Chol]+ and [TMA]+) on triplex DNA, discussing in detail dispersion and hydrogen bonding in addition to Coulomb forces (see Figure 8). As in other biomolecules, the interest in separation and purification has motivated many studies of relative solubility of DNA/RTIL/water.184,185 Separation of DNA fragments has K


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stability) that favor solvation. Water decreases the solubility of polysaccharides in RTILs,201 and for this reason, our discussion of cellulose solvation concerns dry systems. This, however, is not a minor limitation since water is needed for the hydrolysation step that is part of industrial processes that turn cellulose into fuel of chemical feedstock.202 Beyond this general picture, the details of polysaccharide dissolution in RTILs are subtle203−205 and sometimes controversial.206,207 Up to now, the best performance has been measured for [C2mim][CH3(H)PO3] (phosphonate), which has been able to dissolve 2−4 wt % of cellulose at ambient temperature and up to 10 wt % at 45 °C, sufficient to extract cellulose from wood or from bran. All these observations provide the factual basis for applications whose impact could be huge since polysaccharides are by far the most abundant component of biomass.7 Two studies arguably represent the state of the art of investigating microscopic properties of carbohydrates in RTIL systems.208,209 To simplify their task, both studies focused on monosaccharides and used a combination of diffraction experiments and computer modeling. Both neutron and X-ray diffraction, in principle, are powerful techniques to investigate structural properties, but in molecular fluid systems, the interpretation of the data is hampered by the variety of different correlations to be determined by a single diffraction pattern. As already stated in the case of reflectometry, neutrons have an edge with respect to X-rays since isotopic substitution provides a way to generate additional and independent sets of data, making it easier to identify the effect of specific correlations. The difficulty of extracting the relevant information from measurements that combine many different contributions has provided an opportunity for computer modeling that at present plays an essential role in the interpretation of diffraction data. The first of these benchmark experiments208 uses highenergy X-ray diffraction and molecular dynamics to investigate the solvation of the same monosaccharide (glucose) unit into [C2mim][CH3(H)PO3], i.e, the RTIL that dissolves the highest proportion of cellulose (see Figure 9). Glucose concentrations up to 30 wt % have been considered, with measurements carried out at ambient conditions. Computer simulation in the MD approach has been carried out combining an all-atom OPLS force field with the CLaP RTIL force field from ref 24. The experimental scattering intensity was Fourier transformed into a global radial distribution function, combining the contribution of all atomic species. It has been verified that the radial distribution function measured by X-ray diffraction and computed by MD agree well at all distances, apart from small discrepancies possibly due to different glucose isomers (α and β) not accounted for by the simulation. Then, intramolecular and intermolecular contributions have been separated using the MD data. Intermolecular correlations, in turn, have been analyzed into their six independent components (cation−cation, cation−anion, anion−anion, glucose−cation, glucose−anion, and glucose− glucose) using again MD results and starting from the pure RTIL case. This analysis revealed the presence of a short intermolecular distance of 2.6 Å, corresponding to the typical distance between the heavy electronegative atoms in a strong hydrogen bond. According to MD data, this bond is donated by glucose to the anion, while the cation is only second neighbor. As a consequence of the bonding mechanism, and also reflecting the longer glucose−cation distance, it is argued that

also been achieved by electrophoresis in capillaries coated by imidazolium-based RTILs186 Again like in other biomolecules, there is great interest and activity on the nanoscience side aiming at making hybrid systems, joining molecular (ionic) components from nucleic acids, and from RTILs.187 A subject that is likely to acquire progressively more interest is that of DNA and RNA solubility into the so-called deep eutectic solvents DES,188,189 whose general conception has been outlined in the Introduction. An example of DES relevant for our discussion might be solid cholinium chloride and urea or glycerol that in the last case even enjoy the property of being biocompatible.

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IONIC LIQUIDS AND SACCHARIDES Carbohydrates represent a large family of organic compounds of biological interest based on a simple chemical motif, endowed, however, with a rich variety of isomers and a remarkable ability to assemble into polymers of vastly different polymerization degrees. In living organisms, carbohydrates play important roles in energy conversion and storage. Low-weight oligomers are soluble in water and relatively insoluble in most organic solvents. Long polymeric species such as cellulose and chitin are insoluble both in water and in conventional organic solvents since most of their hydrogen-bonding ability is saturated by strong intramolecular and strand−strand hydrogen bonds. The strength of the H-bonding network is reflected in the partial crystallinity of their native structures that contributes to the remarkable resistance to solvation of these biopolymers. Because of their inherent stability, large polysaccharides represent important structural materials. They provide, for instance, the main constituent (chitin) of the exoskeleton of insects and are actively considered as scaffolds for tissue regeneration or even tissue replacement.190,191 Even less extended families of oligomeric saccharides such as cyclodestrins are of interest for pharmaceutical and food applications and also for nanotechnology and nanofabrication in particular.192 Cellulose Solubility into RTILs. The interest in carbohydrate/RTIL interactions has received a decisive boost by the observation that RTILs can dissolve a substantial amount of long carbohydrate polymers (cellulose193,194, chitin195) at temperatures below 100 °C. This process could represent the first major step of cellulose conversion into a valuable feedstock for chemical processing, prior, for instance, to its hydrolysis into simple sugars. The temperature and pressure of dissolution are important to decide the economic and energetic/environmental viability of the process.196,197 Experimental data on the solubility of carbohydrates in RTILs are collected, for instance, in ref 198, spanning a wide range of polymerization degrees. The general picture proposed by the first studies of cellulose dissolution into RTILs, and largely confirmed by further experiments and simulations, is that polarizable anions (chloride, acetate, dimethylphosphate, etc.) eagerly accept Hbonds from the carbohydrate, decreasing the dominant weight of intramolecular and strand−strand H-bonding.194 Noncoordinating anions such as [BF4]− or [PF6]− do not show any remarkable ability to dissolve cellulose. Cations fill a supporting role.199,200 Needless to say, they also interact with the polysaccharide backbone through dispersion forces and sometimes being donors in weak hydrogen bonds, but they mainly screen the charge of the anions H-bonded to the polymeric backbone and contribute to the general chemical physics properties (low viscosity, high chemical, and thermal L


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extensively, producing eight nearly independent scattering intensities over the entire Q range accessible to the spectrometer. As before, modeling relied extensive on MD simulations based on OPLS and CLaP force fields, but in this case, it included a preliminary step in the data-reduction process. More precisely, a MC procedure based on an auxiliary model of neutral and charged Lennard−Jones particles is introduced to ensure that the one-dimensional radial distribution functions or structure factors conform to physical and geometric constraints on the distribution of molecular units in 3D space. In ref 209, this so-called empirical potential structure refinement (EPSR210,211) was used to fit the eight available sets of neutron diffraction data. This complex and somewhat redundant (because of both EPSR and MD) procedure produced two sets of mutually compatible radial distribution functions, one resulting from the neutron scattering data through EPSR modeling and the other directly from atomistic MD modeling, thus validating both the EPSR and the MD data. Moreover, NMR data collected on the same samples confirm the validity of MD estimates for the diffusion coefficient, while 2D nuclear Overhauser effect spectroscopy shows that H-bonding consists only of donations from glucose to the anion, while the protons in the cation and anion do not interact significantly with the glucose hydroxyl groups, at least in this RTIL compounds. Similar results were obtained in ref 208, mutually reinforcing the confidence in each of these two studies. A general conclusion that might be of interest for all RTIL/ biomolecules investigations is the confirmation by refs 208 and 209 that conventional nonpolarizable force fields212 represent a reliable tool to predict structures and to some extent linear transport coefficients. We discussed in detail these two papers as representative of a fairly large number of other contributions, ranging from MD simulations of glucose in [C2mim][Cl] (ref 199) to NMR measurements of the solvation shell around cellobiose molecules in [emim][Ac]213 or COSMO-RS predictions of

Figure 9. Solvation structure of glucose in [C2mim]+[CH3(H)PO3]− ionic liquid investigated by high-energy X-ray diffraction experiments and molecular dynamics (MD) simulations.208 The radial distribution function r2[G(r) − 1], together with (inset) a schematic illustration of the chemical structure.

the glucose−anion bonding is directional, while the glucose− cation is mainly Coulombic and presumably due to charge− dipole coupling. It is important to remark that this detailed structural information is based primarily on the simulation (MD) data. Experiments have been used as a gauge to assess the admissibility of the simulation data. Somewhat enhanced experimental content underlies the second of these two benchmark studies209 using neutron diffraction in combination with NMR and computer modeling to investigate the solvation of glucose monomers into [C2mim][OAc] up to a (mole) proportion of 1:6 glucose to RTIL. In this case, isotopic substitution has been used

Figure 10. (a) Proposed cellulose−IL linking mechanism. (b) Evolution of cellulose Ib bundle in [emim][Ac] showing the unzipping of a single strand (dark gray) after 14 ns of MD simulations. (c) Cellulose Ia bundle in [bmim][Cl] showing contacting chlorides (top row, green) and penetrating cations (bottom row, cyan and white) after 55 ns of MD simulations. Figures from refs 216 and 217. M


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Admittedly, the subject might already be beyond the scope of a single paper, and an exhaustive account of the available literature is no longer feasible nor would it be useful. Nevertheless, by discussing selected examples and by covering a number of other papers, we hope to have provided a representative overview of recent activities on this subject. To make our goal approachable, and for lack of direct experience, we avoided as much as reasonable the strictly biological issues, focusing instead on thermodynamic, structural, and dynamical properties that eventually might allow us to identify the molecular-scale interactions relevant for RTIL/biomolecule systems. This knowledge, not available yet, is required to build predictive approaches for these systems, whose need is apparent from the huge number of RTILs and of biomolecules, not to mention their combinations. For reasons of clarity, our paper has been organized into separate sections concerning RTILs and phospholipids; amino acids, peptides, and proteins; nucleic acids, mainly restricted to DNA; and sugars and polysaccharides of widely different polymerization degrees and spatial organization. Needless to say, overlapping areas among these subtopics, concerning for instance, glyco-proteins, glycolipids, and peptydoglicans, represent the most promising quarries for new discoveries and unforeseen applications. A minimal summary of the present state of the field can be expressed as follows. The largest number of studies arguably concern proteins, also because of the staggering number of systems of interest. The most detailed structural results have been obtained for phospholipids and nucleic acids, while the largest practical impact could result from the successful development of new recipes to dissolve cellulose. This partially crystallized, inedible polymer represents the largest fraction (in mass) of the global and renewable biomass, whose fluidization could ease its conversion in biofuels and plastic materials. As stated in the Introduction, most biomolecules have a welldefined electrostatic signature, and their interaction with electrolytes is predominantly with one of the two ions. Thus, lipids absorb cations; proteins and peptides select their partner according to a charge that depends on chemical parameters such as pH of the physiological solution; nucleic acids are negatively charged and therefore attract cations; sugars have a clear tendency to donate hydrogen bonds (let us consider them as part of the electrostatic interactions) and preferentially bind anions. The size and complexity of the RTIL ions, however, imply that dispersion and steric, but also electrostatic polarization interactions, play a role that, although second to bare Coulomb, is by no means negligible. These effects determine the position and orientation of cations within lipid bilayers, decide the kaotropic or kosmotropic effect of RTIL ions toward protein and peptides, determine the preferential absorption of RTIL cations in the major or minor groove of DNA, and drive the destabilization of the crystal structure of cellulose, leading to its solvation into RTILs and DES.227 The wealth of information already available results from the combined usage of several experimental methods, covering microscopic scales by X-ray and neutron scattering, NMR, optical and vibrational spectroscopy; somewhat longer length scales are the domain of circular dichroism and small angle scattering; the 10 nm to the μ range is explored by AFM and other near-field microscopy approaches; phase diagrams, density, solubilities, and linear transport coefficients are determined by thermodynamic (macroscopic) measurements. A crucial and still growing role in the exploration of RTIL/ biomolecules is played by computational modeling that

ref 214 and calorimetry data on the heat of dissolution of cellulose into [bmim][Ac] reported in ref 215. Besides the investigations of model RTIL/saccharide mixtures, based on simple sugars, simulations of whole cellulose fibers have been carried out, using both atomistic and coarse grained models (see Figure 10).216−219 By and large, the results confirm the insight provided by experiments and simulations of simpler models, although these last miss many of the features, complications, and properties of real fibers, with their variable degree of crystalline ordering. It is worth pointing out that the solvation of mono- and disaccharides in pure ionic liquids not only represents a simple model for the solubility of polysaccharides up to cellulose or chitin, but also it has reasons of interest in itself. At variance from water, RTILs represent suitable solvents for organic reactions, and dissolving oligosaccharides in RTILs represents an important aspect of biorefining, in which saccharide-based feedstock is used to produce a variety of plastic materials. The results of extensive investigation of glucose, fructose, and sucrose solubility in [bmim][N(CN)2] and [bmim][CF3CO2] are reported in ref 220, together with additional calorimetry data and macroscopic (thermodynamic) measurements of density and viscosity. Data are used to parametrize a SAFT (statistical associating fluid theory) equation of state that is able to accurately interpolate the experimental data over a fairly wide range. Not surprisingly, the solubility of even simple sugars in RTILs/water depends sensitively on the RTIL choice and also on the carbohydrate choice, despite the similarity and relative simplicity of several of these carbohydrates. Outlook. Ternary systems such as (small) sugars/RTIL/ water are of obvious interest for separation and purification, food science, and pharmacology. Solubility data are listed in ref 221, while NMR results for the solvation structure and interaction of glucose and carboxylate RTILs in water are reported in ref 222. A broad selection of properties of these systems are discussed in the review of ref 223. ABS separation based on RTILs can be tuned to distinguish even variants (e.g., ketoses and aldoses224) of the same basic sugar. As for other biomolecules, the complexity of structures generated by carbohydrates alone and especially in combination with other species is nearly unlimited, and in many cases, it is possible to tune/improve their properties using RTILs. We only mention the case of chitosan225 and of alginates226 that are intensively investigated for biomedical applications. In the form of glycans, saccharides represent an essential component of glycoproteins that in turn play an important role in biomolecule self-recognition and in a variety of processes involving the rheology of living cells. Their structure and functions often rely on the interplay of hydrophobicity and hydrophilicity, pointing to obvious opportunities of control and manipulation through the addition of RTIL ions adsorbed at the organic/water interface.59 The development of this field might affect nanotechnology.146 Also in the case of saccharides, and polysaccharides in particular, new solvents of the DES family represent a new direction of research in an area closely related to RTILs.227

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SUMMARY AND OUTLOOK FOR THE FUTURE In our contribution to the ACS Sustainable Chemistry & Engineering special issue titled Ionic Liquids at the Interface of Chemistry and Engineering scheduled for February 2016, we endeavored to review chemical physics studies of systems made of biomolecules and room temperature ionic liquids (RTILs). N



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arguably provides the highest resolution view of structures and mechanisms. In its simplest version, simulation pays its resolution by a severe limitation of the scales that it can cover. Because of the size and characteristic times of the systems of interest, in this context, simulation refers primarily to molecular dynamics based on empirical force fields,22−24 covering system sizes up to a few 105 atoms (particles) and time scales up to a few 102 ns. Models of this kind are known to be reliable for biomolecules and for RTILs when considered separately. Their ability to describe RTIL/biomolecule combination could not be given for granted. However, in our discussion, we have encountered many instances in which simulations based on empirical force fields successfully reproduce experimental data. The validation of models and simulation approaches achieved in this way opens the way to a boundless playground of systems and phenomena to be investigated. To some extent, the growing role of the computational approaches rely on the impressive expansion of high performance computer facilities that is still underway. Even more, however, the success of these methods depends on the chemical nature of both RTILs and biomolecules, for which simple models based on particles and bonds are accurate, reliable, and transferable within large families of homologous compounds. The general feeling is that the major ingredient missing from these models and especially for the systems of interest here is electrostatic polarizability, perhaps in a form not covered by traditional polarizable models.228 Eventually, multiscale methods, and coarse-graining models in particular, will open the way to the investigation of macroscopic phenomena and long time scales needed to simulate RTILs interacting with real-life biological structures and to extend the range of meaningful comparisons with experiments. The advances of our knowledge of RTIL/biomolecule systems that might have the largest impact on applications include (i) the simulation of RTILs on real biomembranes, both from healthy and abnormal (cancerous, for instance) cells, made of a mixture of lipids and proteins; pioneering studies have already appeared,229−231 but their relevance is limited by the small size of the simulated systems;232 (ii) the development of models to predict the effect of RTIL ions on the folding and enzymatic activity of proteins in pure and hydrated RTILs; (iii) the understanding of how certain RTILs dissolve amyloid fibrils and, in certain cases, even restore the enzymatic activity of the newly resolvated proteins; (iv) the combination of RTILs and amino acids into hybrid structures, suitable for logic and other electronic devices, including nanowires, switches, and amplifiers; (v) the optimization and enhancement by RTIL addition of the properties of alginate, chitosan, and other ionogels to be used as scaffolds to reconstruct biological tissue and to grow artificial organs. Applications in biophysics, biomedicine, and food science are progressively shifting the interest toward biocompatible RTILs such as those made of a cholinium cations and a deprotonated amino acid anion.18,19,233 The picture emerging from the literature, together with our tentative list of near-future developments, suggests that with RTIL/biomolecule systems we are entering a virtually unlimited research field that could mightily contribute to fulfill the promises of opportunities and reach rewards that so often have sparked the interest and the imagination of the RTIL community.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.B. acknowledges support from the European Community under the Marie Curie Fellowship Grants HYDRA (No. 301463) and PSI-FELLOW (No. 290605), with additional support provided by the School of Physics, University College Dublin, Ireland.

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