Force field refinement for reproducing experimental infrared spectra of ionic liquids.

We employ polarizable molecular dynamics simulations with the newly developed FFGenOpt parametrization tool to reproduce IR spectra of several ionic liquid cations and anions in the gas phase. Our results show that polarizable force fields in the bulk phase provide a reasonable compromise between computational effort and accuracy for investigating IR spectra when treating the transition from gas to liquid phase carefully. Although collectivity seems to play only a minor role, the liquid phase not only changes the electrostatic environment of the molecules but also introduces friction and intermolecular interactions altering the IR spectrum significantly. In addition to the classical force field approach, we also tested if the additional computational effort of machine learning potentials justifies their application in reproducing IR spectra. However, the main purpose of this work is to improve the quality of polarizable force fields concerning vibrations and not the prediction of IR spectra which can be better done with quantum-mechanical cluster approaches.

Emulating proton transfer reactions in the pseudo-protic ionic liquid 1-methylimidazolium acetate.

Proton transfer reactions can enhance conductivity in protic ionic liquids. However, several proton reactions are possible in a multicomponent system of charged and neutral species, resulting in a complex reaction network. Probabilities and equilibrium concentrations of the involved species are modeled by the combination of reducible Markov chains and quantum-mechanical calculations.

Collectivity in ionic liquids: a temperature dependent, polarizable molecular dynamics study.

We use polarizable molecular dynamics simulations to study the thermal dependence of both structural and dynamic properties of two ionic liquids sharing the same cation (1-ethyl-3-methylimidazolium). The linear temperature trend in the structure is accompanied by an exponential Arrhenius-like behavior of the dynamics. Our parameter-free Voronoi tessellation analysis directly casts doubt on common concepts such as the alternating shells of cations and anions and the ionicity. The latter tries to explain the physico-chemical properties of the ionic liquids based on the association and dissociation of an ion pair. However, cations are in the majority of both ion cages, around cations and around anions. There is no preference of a cation for a single anion. Collectivity is a key factor in the dynamic properties of ionic liquids. Consequently, collective rotation relaxes faster than single-particle rotations, and the activation energies for collective translation and rotation are lower than those of the single molecules.

Dielectric spectroscopy and time dependent Stokes shift: two faces of the same coin?

Different types of spectroscopy capture different aspects of dynamics and different ranges of intermolecular contributions. In this article, we investigate the dielectric relaxation spectroscopy (DRS) of collective nature and the time-dependent Stokes shift (TDSS) of disputed nature. Our computational study of unconfined and confined water clearly demonstrates that the TDSS reflects local, non-collective dynamics. Surprisingly, we found that the reaction field continuum model (RFCM) used to estimate TDSS curves solely from collective DRS spectra correctly transforms collective dynamics to local ones even in cases when the relaxation time trends are quite different. This correct transformation is possible due to structural information available in the DRS amplitude in a Kivelsen-Madden like context.

The nuclear Overhauser Effect (NOE) as a tool to study macromolecular confinement: Elucidation and disentangling of crowding and encapsulation effects.

We propose a methodology to capture short-lived but biophysically important contacts of biomacromolecules using the biomolecule-water nuclear Overhauser effect as an indirect microscope. Thus, instead of probing the direct correlation with the foreign biomolecule, we detect its presence by the disturbance it causes in the surrounding water. In addition, this information obtained is spatially resolved and can thus be attributed to specific sites. We extend this approach to the influence of more than one change in chemical environment and show a methodological way of resolution. This is achieved by taking double differences of corresponding σNOE/σROE ratios of the systems studied and separating specific, unspecific, and intermediate influence. While applied to crowding and encapsulation in this study, this method is generally suitable for any combination of changes in chemical environment.

Hydration dynamics of proteins in reverse micelles probed by 1H-NOESY/1H-ROESY NMR and 17O-nuclear quadrupole resonance (NQR).

This study is based on extensive MD simulations of a protein in a reverse micelle to mimic the effect of confinement on biomolecules. This permits the calculation of measurable quantities appearing in NQR and Nuclear Overhauser-NMR despite the high computational effort. We address the long-standing debate about the intermolecular NOE showing that absolute quantities derived from NOESY and ROESY spectra do indeed contain considerable long-range contributions, while ratios thereof are effectively short-ranged due to almost perfect compensation effects. Based on NQR relaxation times, we predict strong rotational retardation of interstitial water between the protein and the surfactant surface. The computed NOE to ROE ratio correlates fairly with experimental results. The solvation dynamics mapped onto the protein surface reflects the spatial heterogeneity of a cell-like system with slow water dynamics in proximity to the cell wall and almost bulk-like behaviour in the water core.

Towards capturing cellular complexity: combining encapsulation and macromolecular crowding in a reverse micelle.

Confinement and macromolecular crowding are acknowledged to be fundamental for the understanding of biomolecular systems. This computational study combines these two phenomena by investigating a multi-protein system encapsulated in a reverse micelle. Contemporary controversies regarding force field accuracy with respect to hydration in such systems were addressed by scaling the non-bonded, non-charged interaction of water with the surfaces, i.e. protein and surfactant (λ-scaling). While based on extensive atomistic simulations, our analysis is of mesoscopic nature with a focus on dielectric properties since recent experimental studies have gained insight on protein mutual orientation via dielectric permittivity. We find two dielectric mechanisms, one allowing for parallel and orthogonal protein dipole alignment while the other leads to preferred anti-parallel alignment. Which mechanism actually occurs is decided by the degree of hydration of both the proteins and the capsule interface. We raise the question whether the findings for reverse micelles can be transferred to biological cells. The embedding in the highly polar outside medium plays an important role in the answer.

The protein-water nuclear Overhauser effect (NOE) as an indirect microscope for molecular surface mapping of interaction patterns.

In this computational study, the intermolecular solute-solvent Nuclear Overhauser Effect (NOE) of the model protein ubiquitin in different chemical environments (free, bound to a partner protein and encapsulated) is investigated. Short-ranged NOE observables such as the NOE/ROE ratio reveal hydration phenomena on absolute timescales such as fast hydration sites and slow water clefts. We demonstrate the ability of solute-solvent NOE differences measured of the same protein in different chemical environments to reveal hydration changes on the relative timescale. The resulting NOE/ROE-surface maps are shown to be a central key for analyzing biologically relevant chemical influences such as complexation and confinement: the presence of a complexing macromolecule or a confining surface wall modulates the water mobility in the vicinity of the probe protein, hence revealing which residues of said protein are proximate to the foreign interface and which are chemically unaffected. This way, hydration phenomena can serve to indirectly map the precise influence (position) of other molecules or interfaces onto the protein surface. This proposed one-protein many-solvents approach may offer experimental benefits over classical one-protein other-protein pseudo-intermolecular transient NOEs. Furthermore, combined influences such as complexation and confinement may exert non-additive influences on the protein compared to a reference state. We offer a mathematical method to disentangle the influence of these two different chemical environments.

Computational spectroscopy of trehalose, sucrose, maltose, and glucose: A comprehensive study of TDSS, NQR, NOE, and DRS.

The bioprotective nature of monosaccharides and disaccharides is often attributed to their ability to slow down the dynamics of adjacent water molecules. Indeed, solvation dynamics close to sugars is indisputably retarded compared to bulk water. However, further research is needed on the qualitative and quantitative differences between the water dynamics around different saccharides. Current studies on this topic disagree on whether the disaccharide trehalose retards water to a larger extent than other isomers. Based on molecular dynamics simulation of the time-dependent Stokes shift of a chromophore close to the saccharides trehalose, sucrose, maltose, and glucose, this study reports a slightly stronger retardation of trehalose compared to other sugars at room temperature and below. Calculation and analysis of the intermolecular nuclear Overhauser effect, nuclear quadrupole relaxation, dielectric relaxation spectroscopy, and first shell residence times at room temperature yield further insights into the hydration dynamics of different sugars and confirm that trehalose slows down water dynamics to a slightly larger extent than other sugars. Since the calculated observables span a wide range of timescales relevant to intermolecular nuclear motion, and correspond to different kinds of motions, this study allows for a comprehensive view on sugar hydration dynamics.

Revival of collective water structure and dynamics in reverse micelles brought about by protein encapsulation.

In this computational study, we investigate the behaviour of a protein in water encapsulated in a zwitterionic/neutral reverse micelle as a cellular mimetic. Addressing the discussion if current force fields are apt to correctly describe crowded/encapsulated environments, we apply an upscaling of the non-bonded, non-electrostatic interactions of protein and/or surfactants with the water component. Based on the thorough analysis of single-particle rotational motion of water and ubiquitin molecules we find retardation near the interfaces and a bulk-like core. This single-particle analysis is contrasted with the study of collective micellar structure and dynamics. We report a novel mechanism of depolarization inside the RM under the general LeChatelier principle of reverse micelle adaptation to the surrounding low-dielectric immersion medium. The relation of this mechanism to other mechanisms of minimum polarization in RMs is discussed.

Micellar confinement disrupts collective structure and accelerates collective dynamics of encapsulated water.

This computational study deals with the collective structure and dynamics as well as their interaction seen from a dielectric viewpoint in zwitterionic reverse micelles for which a force field was designed de novo. For this end, a dualistic strategy is followed: the raw data are generated by extensive microscopic molecular dynamics (MD) simulations while the subsequent analysis has a focus on mesoscopic dielectric properties. The unusually low dielectric signals as well as the remarkable acceleration of collective dynamics is elucidated in great detail. This structural and dynamic behaviour is caused essentially by non-specific micellar boundary conditions. We found that in these ion lacking reverse micelles the water core and the water sheath compensate each other dielectrically which can be understood as a LeChatelier phenomenon facilitating the transition from highly polar encapsulated water to the non-polar low dielectric medium octane. In addition, specific chemical effects are brought about by the perturbing influence of the surfactants. This comprehensive analysis aids both in understanding and designing the dipolar properties of liquid polar spherical colloids dispersed in a hydrophobic medium.

Macromolecular crowding and the importance of proper hydration for the structure and dynamics of protein solutions.

Recent experiments by Weingärtner et al. have given a first hint that dielectric spectroscopy is able to yield a quantitative measure of inter-protein mutual orientation. Therefore, in this computational study, we investigate crowded multi-protein solutions with a special focus on this mutual orientation and its context with dielectric spectroscopy. To the end, existing standard force fields had to be improved by re-scaling the dispersion interaction between protein and water. We find that proper hydration has a strong influence on inter-protein correlations as an enhancement of protein hydration by 10% has a great impact on orientational intermolecular structure. Altogether, the crowding behaviour is improved considerably.

Langevin behavior of the dielectric decrement in ionic liquid water mixtures.

We present large scale polarizable simulations of mixtures of the ionic liquids 1-ethyl-3-methylimidazolium trifluoromethanesulfonate and 1-ethyl-3-methylimidazolium dicyanamide with water, where the dielectric spectra, the ion hydration and the conductivity were evaluated. The dielectric decrement, the depression of the dielectric constant of water upon addition of ions, is found to follow a universal functional of Langevin type. Only three physical properties need to be known to describe the complete range of possible concentrations, namely the dielectric constant of pure water, of pure ionic liquid and the linear slope of the dielectric decrement at low ionic liquid concentrations. Both the generalized dielectric constant, as well as the water contribution to the dielectric permittivity follow the functional dependence. We furthermore find that a scaling of van der Waals parameters upon addition of polarizable forces to the force field is necessary to correctly describe the frequency dependent dielectric conductivity and its contribution to the dielectric spectrum, as well as the static electric conductivity, which is also treated in the framework of a pseudolattice theory.

A shell-resolved analysis of preferential solvation of coffee ingredients in aqueous mixtures of the ionic liquid 1-ethyl-3-methylimidazolium acetate.

Ionic liquids increase the solubility of various coffee ingredients in aqueous solution but little is known about the underlying mechanism. Kirkwood-Buff integrals as well as the potential of mean force indicate that the imidazolium cations are accumulated at the surface of the solutes, removing water molecules from the solute surface. Although hydrogen bonding of the anions to hydroxy groups of the solutes can be detected, their concentration at the surface is less enhanced compared to the cations. The decomposition into solvation shells by Voronoi tessellation reveals that structural features are only observed in the first solvation shell. Nevertheless, the depletion of water and the excess concentration of the ions and, in particular, of the cations are visible in the next solvation shells as well. Therefore, classical arguments of hydrotropic theory fail to explain this behavior.

Towards a complete characterization of the δ-dispersion in dielectric spectroscopy of protein-water systems.

In this computational study, we aim at a complete characterization of the δ-process occurring in dielectric spectroscopy of protein-water systems, with a focus on the consistent interpretation in relation to other experimental observables in the field of biomolecular hydration. A large-scale and long-time molecular dynamics simulation of the protein ubiquitin in aqueous solution offers an adequate basis for the investigation of dielectric properties involving long-ranged and slow collective processes, and their comparison to other experiments calculated from the very same trajectories. An expedient definition of components contributing to the dielectric spectrum reveals at least five different δ-subprocesses. While the previously described cross-correlation between water and protein still plays a major role, we find additional dispersions stemming from protein and water self-correlations. In particular, a contribution of the first hydration shell with moderate retardation relative to bulk water can be linked to the single-particle behavior of water molecules, as observed in magnetic relaxation dispersion. The principle character of the complete δ-process, already once anticipated in experimental literature, is now explicitly calculated and analyzed in great detail, as presented in this study.

Rotational dynamics of water molecules near biological surfaces with implications for nuclear quadrupole relaxation.

Based on Molecular Dynamics simulations of two different systems, the protein ubiquitin dissolved in water and an AOT reverse micelle, we present a broad analysis of the single particle rotational dynamics of water. A comprehensive connection to NQR, which is a prominent experimental method in this field, is developed, based on a reformulation of its theoretical framework. Interpretation of experimental NQR results requires a model which usually assumes that the NQR experiences retardation only in the first hydration shell. Indeed, the present study shows that this first-shell model is correct. Moreover, previous experimental retardation factors are quantitatively reproduced. All of this is seemingly contradicted by results of other methods, e.g., dielectric spectroscopy, responsible for a long-standing debate in this field. Our detailed analysis shows that NQR omits important information contained in overall water dynamics, most notably, the retardation of the water dipole axis in the electric field exerted by a biological surface.

Combining non-equilibrium simulations and coarse-grained modelling allows for a fine-grained decomposition of solvation dynamics.

In this work, we present 4000 independent non-equilibrium molecular dynamics simulations of the time-dependent Stokes shift observed for the chromophore coumarin 153 in the ionic liquid 1-ethyl-3-methylimidazolium trifluoromethanesulfonate. The solvent is simulated using a coarse-grained model, which radically reduces computation demand, while maintaining the anisotropy of shape and charge distribution typical for ionic liquids. Using both, the high number of simulations obtainable with a coarse-grained model as well as the additivity of the non-equilibrium observable, we can study in great detail the origins of the time-dependent Stokes shift in this idealized ionic liquid system. We confirm the previously reported dominant role of the anions and show that the time scales of the relaxation processes for cations and anions are quite different. Additionally, decomposition into contributions from solvation shells defined by Voronoi tessellation clearly demonstrates that only the first two solvation shells contribute to the total effect, while contributions from the bulk solvent almost perfectly compensate and vanish. Furthermore, this decomposition by solvation shells clearly shows that the sub-picosecond relaxation stems almost entirely from the first shell. Owing to the high statistical accuracy, the total Stokes shift can be resolved into contributions from individual solute atoms. This reveals that only 9 out of 36 atoms of coumarin 153 yield significant individual contributions. Even more, two atoms comprise 90% of the total signal.

Dielectric depolarisation and concerted collective dynamics in AOT reverse micelles with and without ubiquitin.

In this computational study we present molecular dynamics (MD) simulations of reverse micelles, i.e. nano-scale water pools encapsulated by sodium bis(2-ethylhexyl) sulfosuccinate (AOT) and dissolved in isooctane. Although consisting of highly polar components, such micro-emulsions exhibit surprisingly low dielectric permittivity, both static and frequency-dependent. This finding is well supported by experimental dielectric measurements. Furthermore, the computational dielectric spectra of reverse micelles with and without the polar protein ubiquitin are almost identical. A detailed component analysis of our simulated systems reveals the underlying mechanism of the observed dielectric depolarisation. While each component by itself would make a remarkable contribution to the static dielectric permittivity, mutual compensation leads to the observed marginal net result. This compensatory behavior is maintained for all but the highest frequencies. Dielectric model theory adapted to the peculiarities of reverse micelles provides an explanation: embedding a system in a cavity engulfed by a low dielectric medium automatically leads to depolarization. In this sense experiment, simulation and theory are in accordance.

Additive polarizabilities in ionic liquids.

An extended designed regression analysis of experimental data on density and refractive indices of several classes of ionic liquids yielded statistically averaged atomic volumes and polarizabilities of the constituting atoms. These values can be used to predict the molecular volume and polarizability of an unknown ionic liquid as well as its mass density and refractive index. Our approach does not need information on the molecular structure of the ionic liquid, but it turned out that the discrimination of the hybridization state of the carbons improved the overall result. Our results are not only compared to experimental data but also to quantum-chemical calculations. Furthermore, fractional charges of ionic liquid ions and their relation to polarizability are discussed.

A computational component analysis of dielectric relaxation and THz spectra of water/AOT reverse micelles with different water loading.

In this computational study, we present molecular dynamics simulations of water/aerosol-OT/isooctane reverse micelles with different water loading. We compare these systems in terms of a detailed analysis of dielectric relaxation spectra and water librations in the THz region. The spectra are decomposed into contributions by molecular species and contributions from individual water solvation shells. Additionally, micellar tumbling motion is shown to have a profound influence on the observed dielectric relaxation spectra, if relaxation by internal reorganization and micellar tumbling occurs within similar time scales. A formalism to directly quantify the effect of micellar tumbling motion on a recorded dielectric spectrum is developed. Since micellar rotational diffusion obeys the laws of hydrodynamics, this method is applicable in an experimental context as well, only knowing the viscosity of the outside medium and the average volume of the reverse micelle.