Conformational Properties of Aß Peptide Oligomers in Aqueous Ionic Liquid Solution: Insights from Molecular Simulation Studies.

Alzheimer's disease is a progressive irreversible neurological disorder with abnormal extracellular deposition of amyloid ß (Aß) peptides in the brain. We have carried out atomistic molecular dynamics simulations to investigate the size-dependent conformational properties of aggregated Aß oligomers of different orders, namely, pentamer [O(5)], decamer [O(10)], and hexadecamer [O(16)] in aqueous solutions containing the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]). The calculations revealed reduced peptide conformational fluctuations in O(5) and O(10) in the presence of the IL. In contrast, the higher order oligomer [O(16)] has been found to exhibit greater structural distortion due to enhanced flexibilities of its peptide units in the presence of the IL. Based on the distributions of the solvent (water) and the cosolvent (IL) components, it is demonstrated that exchange of water by the IL ion pairs at the exterior surface of the oligomers primarily occurs beyond the first layer of surface-bound water molecules. Importantly, a reduced number of relatively weaker peptide salt bridges have been found in O(16) in binary water-IL solution as compared to the other two smaller-sized oligomers [O(5) and O(10)]. Such differential influence of the IL on peptide salt bridges results in less favorable binding free energies of peptide monomers to O(16), which leads to its greater structural distortion and reduced stability compared to those of O(5) and O(10).

Exploring the Heterogeneous Dynamical Environment at the Interface of Aß42 Peptide in Aqueous Ionic Liquid Solution.

In this study, we have investigated the heterogeneous dynamical environment around an ensemble of full-length amyloid-ß (Aß42) peptide monomers in binary aqueous solution containing the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4] as a co-solvent. Atomistic molecular dynamics (MD) simulations have been employed with the aim of understanding the effect of the IL on the distribution of water molecules and IL components around distinct segments of the peptide. As compared to pure aqueous medium, locally heterogeneous restricted water motions at the interface have been spotted in the presence of the IL. Our calculations revealed faster diffusion of water molecules hydrating hydrophilic segments (N-term and turn) as opposed to that around hydrophobic segments (hp1, hp2, and C-term). The extent of non-uniform restriction on the center-of-mass motions as well as the reorientation of water molecules and IL ions have been similarly affected in the binary IL-water solution. The effects of IL on the formation of hydrogen bond networks have been evident from the longer hydrogen bond relaxation time scales of peptide-water, with only a small fraction of peptide-anion hydrogen bonds contributing to the structural relaxation. Due to the size and shape factors, the increasingly sluggish dynamics of the IL components in the solvation shell can be attributed to a longer time scale for the onset of maximum dynamic heterogeneity. Interestingly, the water molecules around the polar segments of the peptide take longer to attain dynamic heterogeneity, which intensifies in the presence of IL. These calculations clearly suggest that electrostatic interaction plays a crucial role in water-mediated peptide-IL interaction, thereby shielding the surface from hydrophobic collapse and preventing possible further growth of the monomers into fibrils at higher peptide concentrations.

Dynamical properties across different coarse-grained models for ionic liquids.

Room-temperature ionic liquids (RTILs) stand out among molecular liquids for their rich physicochemical characteristics, including structural and dynamic heterogeneity. The significance of electrostatic interactions in RTILs results in long characteristic length- and timescales, and has motivated the development of a number of coarse-grained (CG) simulation models. In this study, we aim to better understand the connection between certain CG parameterization strategies and the dynamical properties and transferability of the resulting models. We systematically compare five CG models: a model largely parameterized from experimental thermodynamic observables; a refinement of this model to increase its structural accuracy; and three models that reproduce a given set of structural distribution functions by construction, with varying intramolecular parameterizations and reference temperatures. All five CG models display limited structural transferability over temperature, and also result in various effective dynamical speedup factors, relative to a reference atomistic model. On the other hand, the structure-based CG models tend to result in more consistent cation-anion relative diffusion than the thermodynamic-based models, for a single thermodynamic state point. By linking short- and long-timescale dynamical behaviors, we demonstrate that the varying dynamical properties of the different CG models can be largely collapsed onto a single curve, which provides evidence for a route to constructing dynamically-consistent CG models of RTILs.

Microscopic Understanding of the Effect of Ionic Liquid on Protein from Molecular Simulation Studies.

We have performed molecular dynamics (MD) simulations of the protein α-lactalbumin in aqueous solution containing the ionic liquid (IL) 1-butyl-3-methyl imidazolium tetrafluoroborate ([BMIM][BF4]) as the cosolvent at different concentrations. Attempts have been made to obtain quantitative understanding of the effects of the IL on the conformational features of the protein as well as the distributions of the IL and water around it. The calculations revealed enhanced rigidity of the protein with reduced conformational fluctuations and increasingly correlated local motions in the presence of the IL. Nonuniform relative population of the BMIM+ and BF4- ions at the protein surface with respect to that in the bulk solution has been observed. It is demonstrated that exchange of water by the IL around the protein results in rearrangement of the hydrogen bond network at the interface with breaking of protein-water hydrogen bonds and formation of protein-IL hydrogen bonds. Importantly, it is found that the protein forms increased number of stronger salt bridges in the presence of IL. This shows that the formation of a greater number of such stronger salt bridges is the origin behind the enhanced rigidity of the protein in the presence of the IL.

On the relevance of electrostatic interactions for the structural relaxation of ionic liquids: A molecular dynamics simulation study.

We perform molecular dynamics simulations to investigate the structural (α) relaxation of models of 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim][PF6]) room temperature ionic liquids. To determine the relevance of electrostatic interactions for the dynamical properties, we systematically scale the partial charges of the ions. Observing the structural relaxation of these charge-scaled ionic liquids from high temperature far above the melting point to low temperatures in the viscous regime, we find that the α-relaxation times τq strongly depend on the strength of the electrostatic interactions. The glassy slowdown τq(T) of all systems is successfully described by splitting the apparent activation energies E(T) into a temperature-independent contribution E∞, which characterizes the α relaxation of the high-temperature liquid, and a temperature-dependent contribution Ec(T), which describes the growing cooperativity and increases exponentially upon cooling. For all used partial charges, we find a common relation between the activation energy E∞ and the glass transition temperature Tg, indicating a close link between simple-liquid and viscous-liquid dynamics. To ascertain the origin of the increase of the cooperative contribution Ec(T), we characterize the evolution of space-time characteristics of dynamical heterogeneities upon cooling. It turns out that the length and time scales of spatially heterogeneous dynamics are the same for all studied charge-scaled ionic liquids when plotted as function of τq. Moreover, we find a common relation between Ec and the size of transient clusters of highly mobile ions.

Role of Dynamic Heterogeneities in Ionic Liquids: Insights from All-Atom and Coarse-Grained Molecular Dynamics Simulation Studies.

We performed molecular dynamics simulations for the room-temperature ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim][PF6 ]). By employing all-atom (AA) and coarse-grained (CG) models, we compared the characteristic times of various dynamical modes, from vibration to diffusion, and the importance of dynamical heterogeneities at different levels of chemical resolution and over broad temperature ranges. It was shown that coarse graining leads to a substantial speedup in molecular dynamics, whereas it weakly affects the strength of dynamical heterogeneities. Despite the general speedup, several relationships between dynamical modes on different timescales were preserved. In particular, the heterogeneity timescales of the AA and CG models collapse onto the same curve as a function of the structural (α) relaxation time τα . Moreover, vibrational amplitudes and relaxation times τα are related at both levels of chemical resolution. We argue that the robustness of these relationships assists the development of dynamically consistent coarse-graining strategies and justifies the use of simplified models for a theoretical understanding of viscous liquids.

Composition Dependence of Dynamic Heterogeneity Time- and Length Scales in [Omim][BF4]/Water Binary Mixtures: Molecular Dynamics Simulation Study.

Composition dependence of four-point dynamic susceptibilities, overlap functions, and other dynamic heterogeneity (DH) parameters have been investigated by using all-atom molecular dynamics simulations for aqueous solutions of the ionic liquid (IL), 1-octyl-3-methyl imidazolium tetrafluoroborate ([Omim][BF4]) covering the pure-to-pure range. Upon addition of water in the IL, the DH time scales become faster and the four-point dynamic susceptibility time scale softens. Evidences for jump motions for both water and ions have been found from the simulated single particle displacements that show strong deviation from Gaussian distribution. Estimated dynamic correlation length for water reflects effects of IL, whereas those for ions remain largely insensitive to the mixture composition. Simulated structural aspects and DH time scales provide microscopic explanations to the existing experimental observations from time-resolved fluorescence and Kerr spectroscopic measurements.

Stokes shift dynamics in (non-dipolar ionic liquid + dipolar solvent) binary mixtures: a semi-molecular theory.

A semi-molecular theory for studying composition dependent Stokes shift dynamics of a dipolar solute in binary mixtures of (non-dipolar ionic liquid + common dipolar solvent) is developed here. The theory provides microscopic expressions for solvation response functions in terms of static and dynamic structure factors of the mixture components and solute-solvent static correlations. In addition, the theory provides a framework for examining the interrelationship between the time dependent solvation response in and frequency dependent dielectric relaxation of a binary mixture containing electrolyte. Subsequently, the theory has been applied to predict ionic liquid (IL) mole fraction dependent dynamic Stokes shift magnitude and solvation energy relaxation for a dipolar solute, C153, in binary mixtures of an ionic liquid, trihexyltetradecylphosphonium chloride ([P(14,666)][Cl]) with a common dipolar solvent, methanol (MeOH). In the absence of suitable experimental data, necessary input parameters have been obtained from approximate methods. Dynamic shifts calculated for these mixtures exhibit a linear increase with IL mole fraction for the most part of the mixture composition, stressing the importance of solute-IL dipole-ion interaction. Average solvation rates, on the other hand, show a nonlinear IL mole fraction dependence which is qualitatively similar to what has been observed for such binary mixtures with imidazolium (dipolar) ILs. These predictions should be re-examined in suitable experiments.

Slow solvation in ionic liquids: connections to non-Gaussian moves and multi-point correlations.

This paper explores an interconnection between timescales of dynamic heterogeneity (DH) in a neat ionic liquid (IL), 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim][PF6]), and slow solvation of a dipolar solute, coumarin 153 (C153) in it at 298 K and 450 K. Molecular dynamics simulations employing realistic interaction potentials for both the IL and the solute have been performed. DH timescales have been obtained from non-Gaussian and new non-Gaussian (NNG) parameters, and four-point dynamic susceptibilities (χ4(k, t)) and overlap functions (Q(t)). Simulated ion displacement distributions exhibit pronounced deviations from Gaussian behaviour and develop bimodality in the timescale of structural relaxation, τ(α), indicating ion hopping at long-time. DH timescales from χ4(k, t) and Q(t) have been found to be longer than τ(NNG) although τ(α) ≈ τ(NNG). Maximum cation jump length detected here corresponds to ~50% of the ion diameter and agrees well with experimental estimates. DH length-scale (ξ) extracted from χ4(k, t) spans about an ion diameter and shows correct temperature dependence. Our simulated solvation response functions for C153 in [Bmim][PF6] are tri-exponentials with fast time constants in good agreement with the available experimental and/or simulation data. The slow solvation rate at 298 K, however, is ~4 times slower than that found in experiments, although the same at 450 K corroborates well with simulation data at similar temperature from different sources. Importantly, our simulated slow solvation rates at these temperatures strongly correlate to longer DH timescales, suggesting DH as a source for the slow solvation at long-time in IL. Moreover, ion jumps at long-time suggests viscosity decoupling of long-time solvation rate in ILs.

Stokes shift dynamics of ionic liquids: solute probe dependence, and effects of self-motion, dielectric relaxation frequency window, and collective intermolecular solvent modes.

In this paper we have used a semi-molecular theory for investigating the probe dependence of Stokes shift dynamics in room temperature ionic liquids (ILs) by considering three different but well-known dipolar solvation probes--coumarin 153, trans-4-dimethylamino-4(')-cyanostilbene, and 4-aminophthalimide. In addition, effects on polar solvation energy relaxation in ILs of solute motion, frequency coverage (frequency window) accessed by dielectric relaxation measurements and collective IL intermolecular modes (CIMs) at tera-hertz range have been explored. Eleven different ILs have been considered for the above theoretical study. Calculated results show better agreement with the recent (fluorescence up-conversion (FLUPS) + time-correlated single photon counting (TCSPC)) experimental results, particularly at short times, when the CIM contribution to the frequency dependent dielectric function (ɛ(ω)) is included. This is done via assigning the missing dispersion in an experimental ɛ(ω) to an IL intermolecular mode at 30 cm(-1). No significant probe dependence has been observed for solvation energy relaxation although the magnitude of dynamic Stokes shift varies with the dipole moment of the excited solute. Calculations using experimental ɛ(ω) measured with broader frequency window generate solvation response functions closer to experiments. However, average solvation rates predicted by using different ɛ(ω) for the same IL do not differ appreciably, implying over-all validity of these dielectric relaxation measurements. Results presented here indicate that inclusion of solvent molecularity via wavenumber dependent static correlations and ion dynamic structure factor relaxation improves significantly the comparison between theory and experiments over the continuum model predictions for polar solvation dynamics in these solvents.