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.

Collective Spectroscopy of Solvation Phenomena: Conflicts, Challenges, and Opportunities.

Different spectroscopy types reveal different aspects of molecular processes in soft matter. In particular, collective observables can provide insights into intermolecular correlations invisible to the more popular single-particle methods. In this perspective we feature the dielectric relaxation spectroscopy (DRS) with an emphasis on the proper interpretation of this complex observable aided by computational spectroscopy. While we focus on the history and recent advances of DRS in the fields of biomolecular hydration and nanoconfinement, the discussion transcends this particular field and provides a guide for how collective spectroscopy types supported by computational decomposition can be employed to further our understanding of soft matter phenomena.

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.

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.

The Intermolecular NOE Depends on Isotope Selection: Short Range vs Long Range Behavior.

The nuclear Overhauser effect (NOE) is a powerful tool in molecular structure elucidation, combining the subtle chemical shift of NMR and three-dimensional information independent of chemical connectivity. Its usage for intermolecular studies, however, is fundamentally limited by an unspecific long-ranged interaction behavior. This joint experimental and computational work shows that proper selection of interacting isotopes can overcome these limitations: Isotopes with strongly differing gyromagnetic ratios give rise to short-ranged intermolecular NOEs. In this light, existing NOE experiments need to be re-evaluated and future ones can be designed accordingly. Thus, a new chapter on intermolecular structure elucidation is opened.

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.

Understanding the Nature of Nuclear Magnetic Resonance Relaxation by Means of Fast-Field-Cycling Relaxometry and Molecular Dynamics Simulations-The Validity of Relaxation Models.

Fast-field-cycling relaxometry is a nuclear magnetic resonance method growing in popularity; yet, theoretical interpretation is limited to analytical models of uncertain accuracy. We present the first study calculating fast-field-cycling dipolar coupling directly from a molecular dynamics simulation trajectory. In principle, the frequency-resolved dispersion contains both rotational and translational diffusion information, among others. The present joint experimental/molecular dynamics study demonstrates that nuclear magnetic resonance properties calculated from the latter reproduce measured dispersion curves and temperature trends faithfully. Furthermore, molecular dynamics simulations can verify interpretation model assumptions by providing actual diffusion coefficients and correlation times.

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.

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.

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.

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.

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.

Changes in protein hydration dynamics by encapsulation or crowding of ubiquitin: strong correlation between time-dependent Stokes shift and intermolecular nuclear Overhauser effect.

The local changes in protein hydration dynamics upon encapsulation of the protein or macromolecular crowding are essential to understand protein function in cellular environments. We were able to obtain a spatially-resolved picture of the influence of confinement and crowding on the hydration dynamics of the protein ubiquitin by analyzing the time-dependent Stokes shift (TDSS), as well as the intermolecular Nuclear Overhauser Effect (NOE) at different sites of the protein by large-scale computer simulation of single and multiple proteins in water and confined in reverse micelles. Besides high advanced space resolved information on hydration dynamics we found a strong correlation of the change in NOE upon crowding or encapsulation and the change in the integral TDSS relaxation times in all investigated systems relative to the signals in a diluted protein solution.

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.

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.

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.

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.

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.

Revival of the Intermolecular Nuclear Overhauser Effect for Mapping Local Protein Hydration Dynamics.

The highly heterogeneous hydration dynamics of protein-water interfaces is considered important for protein stability and dynamics, protein folding, enzymatic activity, and even drug design. The nuclear Overhauser effect (NOE) between protein and water protons is the only experimental observable which, in principle, can provide a map of locally resolved hydration dynamics. However, its utility was questioned in various theoretical studies that emphasized the contributions of long-range NOE interactions. We show by a detailed analysis based on molecular dynamics simulations that, contrary to recent claims, the protein-water NOE is an excellent observable to map local hydration dynamics at the protein surface.