Mechanical Stretching of Nature Inspired Linear and Branched Polysaccharide Motifs through Steered Molecular Dynamics.

A variety of 10 polysaccharide motifs comprising naturally inspired sequences of monosaccharide building blocks are studied to understand the inter-relation between their structural and mechanical behaviors. Equilibrium and steered molecular dynamics (SMD) simulations are employed to investigate the stress-strain relationships and the associated conformational flips of the pyranose moieties along the polysaccharide chains. The presence of a variety of glycosidic linkages connecting the diverse monosaccharide units along with chain-branching in some cases induce wide diversity in the carbohydrate-Ramachandran plots of the glycosidic dihedrals. Similar variations are observed in the Cremer-Pople ring puckering patterns across the polysaccharide variants. The work further provides a comparison between the experimentally obtained atomic force microscopic data of mechanical stretching for some polysaccharides with the stress-strain curves generated from our SMD simulations. Out of all the systems studied, pectin having an axial-axial orientation of the glycosidic linkage showed maximum stretching potential, while acetan-M, with an equatorial-equatorial disposition of the glycosidic bond, stretched the least. The experimental Young's modulus of the corresponding natural polysaccharides could be reasonably compared to the values obtained from our simulation models. Force distribution analysis is done to understand the propagation of punctual stress in the polysaccharides under SMD conditions. Changes in local electrophilicity or nucleophilicity of atomic centers in puckered pyranose rings are estimated through the condensed Fukui functions. All of this information can help understand the physical behavior and chemical reactivity of complex polysaccharides in a complicated milieu of electronic and steric effects experienced by them.

HSA over BSA: Selective detection of Human Serum Albumin via a naphtho [2,1-b] furan-based system.

Human serum albumin (HSA) is an important biomarker that can be used for the early diagnosis of many diseases. In this work, a TICT probe bearing fused naphtho-furan scaffold (NPNF) was developed and employed in the selective turn-on sensing of HSA. The probe's selectivity towards HSA was observed using steady-state fluorescence experiments, with limit of quantitation in micromolar levels. NPNF's capability to exclusively detect HSA over BSA was further studied/rationalized using anisotropy and time-resolved studies. Molecular docking was used to shed light on the location of NPNF in the subdomain IB of HSA. The practical application of the probe was also demonstrated by the detection of HSA in urine and the HSA-assisted detection of cerium.

Robustness of heteroaggregates involving hydrophobic cholesterol and its mimetics.

Exploring the self and cross aggregation affinity of cholesterol (CHL) and some of its lookalikes, e.g., cholesteryl hemisuccinate (CHM), campesterol (CAM) and arjunic acid (ARJ), provides crucial understanding towards the influence of weak forces in inducing mixed micellization through heteroaggregation. Strongly hydrophobic CHL, with a benchmark inclination towards aggregation, often forms detrimental plaques in crucial human organs that are fairly difficult to disintegrate. Traditionally known anti-dyslipidemic agents like CAM and ARJ are known to interact strongly with CHL in the gut when ingested. They further form mixed micelles along with the bile components and interfere with the CHL absorption across the epithelial cell layer of the intestine. Some invariant questions like how robust are the heteroaggregates formed between these mimetics and CHL are very important to appreciate the efficacy of such anti-dyslipidemic agents. In this work using molecular dynamics simulations and varied structural analysis, we characterize the heteroaggregates. Simulations indicate that CHL-CHM mixed assemblies are comparatively bigger and significantly stabilized by strong electrostatic and favourable vdW forces. Small and diffused CHL-ARJ aggregates are observed in our simulations with a not so favourable energetics, indicating a possible attenuation pathway of CHL aggregation in the presence of ARJ.

Free energy landscape of wrapping of lipid nanocluster by polysaccharides.

Wrapping of a 20-mer cholesterol nano-cluster (CHL-nanoC) by two widely different types of ß-glucan polysaccharides (23-25 mers) having significantly varying glycosidic linkage patterns and side chains is studied by Well-Tempered MetaDynamics (WT-MetaD) simulations. The problem has its relevance in the faecal sterol and bile acid excretion in humans and the role of dietary fibres in aiding the process and combating dyslipidemia. Additionally, the distinctive collective variables studied here can be extended for modeling of polymer wrapped soft clusters/nano-particles in general. The wrapping ability is observed to be significantly correlated to the bending of the polysaccharide chain, an attribute of the glycosidic linkage type. By biasing two unique collective variables, the radius of gyration of the polysaccharide (Rg, poly) and the second order Legendre polynomial of the segment orientation parameter, θ, we could successfully observe the wrapping process. This work compares in detail the physical properties of the polysaccharide encapsulated CHL-nanoC by probing the radius of curvature (Rcurv, poly) of the polysaccharides, their coordination number with respect to the CHL-nanoC (CN), fractional CHL-nanoC surface coverage and the electrostatic surface potentials of the complex assembly. Results indicate that the ß-glucan having 1-4 glycosidic linked monomers with intermittent 1-3 linkage is able to wrap the CHL-nanoC more effectively. The 1-3 glycosidic linked ß-glucan with 1-6 glycosidic bonds in side chains is significantly curled up and appears to be less efficient in wrapping the nanoC. This work provides a comparative molecular level picture of mutual interaction between two major dietary polysaccharide variants and lipid globules as indicated by numerous clinical level studies involving mice and human models.

Monosaccharide induced temporal delay in cholesterol self-aggregation.

Self-assembly of cholesterol (CHL) is infamous for its diverse deleterious effects on human health. Clinical research over several decades indicates that a diet rich in CHL typically leads to arterial plaques, cataracts and gall stones among others. Carbohydrates like the ß-glucans efficiently lower serum CHL, possibly by inhibiting CHL absorption in the digestive tract. Using molecular dynamics simulations, we explore how ß-D-glucose (BGLC), the building block of ß-glucans, interferes with CHL aggregation. BGLC slows down CHL diffusion and disrupts the formation of the robust hydrophobic CHL assembly. Estimation of the translational entropy of the CHL molecules shows the extent of retardation induced by BGLC. Coordination numbers obtained from the adjacency matrix and collective variable analysis of the packing of the CHL molecules in presence of BGLC show the time evolution of CHL aggregation. In presence of BGLC, small isolated CHL islands form, consolidate and disintegrate over time as compared to the blank CHL system. The predominance of smaller CHL clusters is an effect of the significant retardation of the translational motion of CHL molecules induced by BGLC.Communicated by Ramaswamy H. Sarma.

Cyclic cystine knot and its strong implication on the structure and dynamics of cyclotides.

The archetypal Viola odorata cyclotide cycloviolacin-O1 and its seven analogs, created by partial or total reduction of the three native S-S linkages belonging to the "cyclic cystine knot" (CCK) motif are studied for their structural and dynamical diversities using molecular dynamics simulations. The results indicate interesting interplay between the constraints imposed by the S-S bonds on the dynamical modes and the corresponding structure of the model peptide. Principal component analysis brings out the variation in the extent of dynamical freedom along the peptide backbone for each model. The motions are characterized by low amplitude diffusive modes in the peptides retaining most of the native S-S linkages in contrast to the large amplitude discrete jumps where at least two or all of the three S-S linkages are reduced. Simulation results further indicate that the disulfide bond between Cys1-18 is formed at a much faster pace compared with its two other peers Cys5-20 and Cys10-25 as found in the native peptide. This gives insight as to why the S-S linkages appear in the native peptide in a particular combination. Model therapeutics and drug delivery engines can potentially utilize this information to customize the engineered S-S bonds and gauge its impact on the dynamic flexibility of a model macrocyclic peptide.

Structural and spectroscopic details of polysaccharide-bile acid composites from molecular dynamics simulations.

Interactions of a prototypical bile acid (cholic acid, 'Ch') and its corresponding sodium salt (sodium cholate, 'NaCh') with a standard dietary ß-glucan (ß-G), bearing ß-D-glucopyranose units having mixed 1-4/1-3 glycosidic linkages are studied using molecular dynamics simulation and density functional theory (DFT) calculations. Self-aggregation of the biliary components and their interaction with fifteen strands of the decameric mixed linkage ß-glucan is elucidated by estimating varieties of physical properties like the coordination number, moment of inertia and shape anisotropy of the biggest cluster formed at different time instants. Small angle scattering profiles indicate formation of compact spheroidal aggregates. The simulated results of small angle scattering and 1H NMR chemical shifts are compared to spectroscopic data, wherever available. Density functional theory calculations and estimation of the 1H NMR chemical shifts of Ch-protons lying close to the ß-G chains reveal change in chemical shift values from that in absence of the polysaccharide. Hydrogen bonding and non-bonding interactions, primarily short range van der Waals interactions and some extent of inter-molecular charge transfer are found to play significant role in stabilizing the complex soft assemblies of bile acid aggregates and ß-G.Communicated by Ramaswamy H. Sarma.

Copper acetate catalysed C-C bond formation en route to the synthesis of spiro indanedione cyclopropylpyrazolones.

This article reports the synthesis of spiro compounds based on an indanedione-cyclopropane-pyrazolone framework. The reaction relied upon the Michael-initiated ring closure strategy and was carried out under Cu(OAc)2 catalysis, assisted by an oxygen atmosphere and the base Et3N. The final compounds were obtained as an inseparable mixture in most cases with modest to good yields using diverse substrates. Among the two plausible routes, computational studies indicated the feasibility of a route which involves a four-membered Cu containing intermediate. Given the generic nature of the developed method, it may be utilised to synthesise other analogous spiro systems.

Relation between glycosidic linkage, structure and dynamics of α- and ß-glucans in water.

In a molecular dynamics simulation study of several oligosaccharides comprising of the very basic building block of carbohydrate, the α- or ß-d glucopyranose units, linked by any one of the 1-3/1-4 or 1-6 glycosidic linkages, we compare and contrast their structural and dynamical properties. Results indicate that the litheness of the oligosaccharide chain is noticeably controlled by the composition, anomeric nature and glycosidic linkage type of the units. In mixed ß 1-4/1-3 d-glucopyranosides, as those found in oats and barley, the ratio of the ß 1-4 and ß 1-3 linked residues is crucial in determining the structural and dynamical attributes. Principal component analysis (PCA) using the internal coordinates of torsion angles subtended by glycosidic oxygen atoms and subsequent K-means clustering of the dynamical space spanned by PC1 to PC2 point to the dynamical and structural disparity in the various types of oligosaccharides studied. The properties simulated in this work are meant to provide a systematic yet comparative understanding of the importance of linkage and anomericity on the oligosaccharide chain properties and are in line with some experimental structural attributes.

Distinctive Weak Interactions Underlie Diverse Nucleation and Small-Angle Scattering Behavior of Aqueous Cholesterol, Cholesteryl Hemisuccinate, and Glycocholic Acid.

Increased total cholesterol is a major cause of serious heart ailments leading to an estimated 3 million deaths annually throughout the world. Understanding the flocculation behavior of small lipids is thus quintessential. Nucleation, small-angle scattering, and dynamical behavior of lipids and analogues like cholesterol (CHL), cholesteryl hemisuccinate (CHM), and glycocholic acid (GHL) are studied in water by molecular dynamics simulation. The study shows a distinct aggregation behavior of these physiologically relevant molecules owing to a systematic gradation in their non-bonding interactions with solvents and near neighbors. Spontaneous self-assemblies formed during simulation are observed to have different stability, aggregation patterns, and dynamics depending crucially on the nature of the hydrophobic/hydrophilic tails. With increasing hydrophilicity, in the order CHL < CHM < GHL, the aggregates become breakable and less compact, often interposed by water molecules in the interstitial spaces between the lipids. Small-angle scattering data obtained from our simulations provide insights toward the structural integrity and shape of the aggregates formed. Unique features are noticed while following the time evolution of the packing of the nucleated assemblies from the solution phase in terms of local density and molecular orientation. As hydrophilicity increases from CHL to GHL, the packing becomes progressively erratic with diverse angles between the molecular vectors. Surface electrostatic potential calculation indicates drastic increase in positive surface charge from CHL to CHM, which has strong implication in water and ion transport through membranes. These observations can be further correlated to comprehend the flocculation of cholesterol and bile acids in the human body.

Positional Variation of Monopyridyl-N in Unsymmetrical Anthracenyl π-Conjugates: Difference between Solution- and Aggregate-State Emission Behavior.

Fluorescence enhancement on aggregation for π-conjugates linked with pyridyl ring has been established as a part of widely studied smart organic functional materials. Therefore, the photophysical features in the solution and aggregate states for such compounds remain impressive. In this work, we synthesized three series of photostable unsymmetrical aryl-substituted anthracenyl π-conjugates linked to pyridyl ring with a variation of the position of a pyridyl-N atom and examined the difference in the photophysical properties preferably in the aggregate state. The so-called "aggregation-induced emission (AIE)" behavior was discernible for the 2- and 4-pyridyl- but not 3-pyridyl-10-p-tolyl or mesityl-substituted π-conjugates. Curiously, a variation of the position of a pyridyl-N atom does not solely control the AIE phenomenon for 10-thiophenyl-substituted π-conjugates, where all of the isomers are found to be AIE-active. Hence, the dissimilarity in emission behavior in the aggregate state is governed by the position of N-atom for pyridine and also the substituent at the 10th position of the anthracyl ring. The mechanistic insight behind these observations is demonstrated by concentration-dependent fluorescence studies, time-resolved fluorescence, single-crystal X-ray diffraction studies (largely supportive to understand the molecular structure and packing in the aggregate), and average particle size measurement of the aggregates and partly by the density functional theory studies for a few representative molecules.

Principal Component Analysis of a Conotoxin Delineates the Link among Peptide Sequence, Dynamics, and Disulfide Bond Isoforms.

Replica exchange molecular dynamics (REMD) and subsequent principal component analysis (PCA) of the dynamical modes of α-conotoxins, GI and its two mutants, in water and an aqueous biocompatible ionic liquid, 1-ethyl-3-methyl-imidazolium acetate (50%, v/v), provide perceptions into how the mutations affect the global correlated motions in the peptide backbone, eventually ending up influencing the combination of disulfide links in such multiple cysteine-containing venom toxins. Region-wise breakup of the contribution of the three peptides to the first two principal components (PCs) reveals disparate dynamical patterns in water and a water-ionic liquid mixture. Additionally, K-means clustering within the conformation space spanned by PC1 and PC2 compares and contrasts the different peptide-solvent systems, sorting further the disulfide bond isoforms into specific clusters. In each cluster, and also in a particular disulfide bond isoform, an estimation of the amino acid block loadings toward PC1 and PC2 helps relate the mutations in the GI sequence to targeted synthesis of a given isoform in a given solvent system.

Peptide Sequence and Solvent as Levers to Control Disulfide Connectivity in Multiple Cysteine Containing Venom Toxins.

Judicious choice of solvent, temperature, and strategic mutations along a peptide backbone can minimize formation of non-native disulfide bond isoforms in chemical synthesis of multiple cysteine containing venom toxins. By exploiting these controls, one can drive the population distribution in favor of a particular isoform. Some chosen ionic liquids (ILs), like 1-ethyl-3-methyl-imidazolium acetate, [Im21][OAc], have proven efficient in favoring the native globular isoform in some conotoxins. To comprehend such a preference, we report an explicit solvent replica exchange molecular dynamics (REMD) study of two conotoxins, AuIB and GI, solvated in either neat water or ∼50% (v/v) mixture of water-[Im21][OAc]. Our simulations indicate that compared to neat water, the probability of obtaining native globular isoform of AuIB significantly increases in a water-IL mixture at 305 K. Strikingly, and aligned with experimental observations, peptide GI does not favor the native connectivity in the water-IL mixture. In presence of IL, strong solvent mediated fluctuations of the GI backbone are observed in our simulations. Uneven ion accumulation along the backbone owing to strong H-bonding interactions of some GI residues with IL ions, especially the anion OAc-, restricts conformational freedom of the peptide. Estimation of backbone entropy and Helmholtz free energy corroborates the lack of conformational freedom in GI as compared to AuIB, especially in the presence of IL. In line with prior experiments, simulations of GI mutants indicate that one could possibly force a given pair of Cys residues to come closer by strategically mutating GI residues with glycine and/or alanine, resulting in the breakage/formation of helix-like motifs.

Aqueous ionic liquids influence the disulfide bond isoform equilibrium in conotoxin AuIB: a consequence of the Hofmeister effect?

The appearance of several disulfide bond isoforms in multiple cysteine containing venom peptides poses a significant challenge in their synthesis and purification under laboratory conditions. Recent experiments suggest that careful tuning of solvent and temperature conditions can propel the disulfide bond isoform equilibrium in favor of the most potent, native form. Certain aqueous ionic liquids (ILs) have proven significantly useful as solvents for this purpose, while exceptions have also been noted. To elucidate the molecular level origin behind such a preference, we report a detailed explicit solvent replica exchange molecular dynamics study of a conotoxin, AuIB, in pure water and four different aqueous IL solutions (~45-60% v/v). The ILs studied here are comprised of cations like 1-ethyl-3-methyl-imidazolium (Im21+) or 1-butyl-3-methyl-imidazolium (Im41+) coupled with either acetate (OAc-) or chloride (Cl-) as the counter anion. Our simulations unfold interesting features of the conformational spaces sampled by the peptide and its solvation in pure water and aqueous IL solutions. Detailed investigation into populations of the globular disulfide bond isoform of AuIB in aqueous IL solutions reveal distinct trends which might be related to the Hofmeister effect of the cation and anion of the IL and of specific interactions of the aqueous IL solutions with the peptide. In accordance with experimental observations, the aqueous [Im21][OAc] solution is found to promote the highest globular isoform population in AuIB.

Weak Donor-/Strong Acceptor-Linked Anthracenyl π-Conjugates as Solvato(fluoro)chromophore and AEEgens: Contrast between Nitro and Cyano Functionality.

Steady development on photophysical behaviors for a variety of organic fluorophores inspired us to generate anthracene-based fluorescent molecules with a strong acceptor and a significantly weak donor through a π-spacer. Such molecules are found to have substantial twisted conformational orientations in the solid state and enhanced apolar character because of the attachment of tolyl or mesityl group with an anthracenyl core. Upon exposure to a variety of solvents, strong solvatochromism was noticed for 4-nitro compound (84 nm red shift) in contrast to the cyano analogue (18 nm red shift). Both these probes were highly emissive in apolar solvents while nitro-analogue, in particular, could discriminate the solvents of E T(30) (a measure of microscopic solvent polarity) ranging from 31 to 37. Thus, 4-nitro compounds can be successfully employed to detect and differentiate the apolar solvents. On the contrary, the 2-nitro analogue is almost nonemissive for the same range of solvents perhaps because of favorable excited-state intramolecular proton-transfer process. The fundamental understanding of solvatochromic properties through the formation of twisted intramolecular charge-transfer (TICT) state is experimentally analyzed by synthesizing and studying the π-conjugates linked to only benzene in place of nitro or cyanobenzene, which exhibits no solvatochromism and that helped finding the possible emission, originated from the locally excited state. Moreover, the molecular structures for these compounds are determined by the single-crystal X-ray diffraction studies to examine the change in emission properties with molecular packing and alignment in the aggregated state. The measurement of dihedral angles between the substituents and anthracenyl core was helpful in finding the possible extent of electronic conjugations within the system to decipher both solvatochromism and aggregation enhanced emission (AEE)-behavior. The cyano analogue exhibited prominent AEE-behavior, whereas nitro analogues showed the aggregation-caused quenching effect. The reason behind such dissimilarity in solvatochromism and AEE-behavior between cyano- and nitro-linked anthracenyl π-conjugates are also addressed through experimental outcomes.

Temperature-dependent molecular dynamics study reveals an ionic liquid induced 310 - to α-helical switch in a neurotoxin.

Thermal melting and recooling of AuIB, a neurotoxic conopeptide and a highly potent nonaddictive pain reliever is investigated thoroughly in water and an ionic liquid (IL) 1-butyl-3-methylimidazolium Chloride, [Im41 ][Cl] by classical molecular dynamics simulations. Structural evolution of AuIB in water and the IL is observed at different temperatures between 305 and 400 K, to explore how highly viscous ionic solvents affect the peptide structure as compared to conventional solvent water. At 305 K, unlike water, the coercive effect of IL frustrates AuIB secondary structural motifs significantly. As the temperature is raised, a very interesting IL induced conformational transition from 310 - to α-helix is noticed in the peptide, presumably triggered by a significant restructuring of the peptide H-bond network. The backbone length distributions of the peptide indicate that the IL induced conformational switching is accompanied by a reduction of the axial rise of the helical region, encompassing the residues Pro-6 to Ala-10. Further, we estimated the void space available to the peptide for its structural relaxation within the first solvation shell of ∼5 Å in water as well as in IL. A temperature increase by 100 K, opens up an estimated void volume of ∼70 Å3 , equivalent to the volume of approximately six water molecules, around the peptide in IL. Cooling simulations of AuIB point to the crucial interplay between thermodynamically favored AuIB conformers and their kinetic control. This study provides a comprehensive understanding of the ionic solvation of biomolecules reinforcing previous experimental findings.

Scrambling of disulfide bond scaffolds in neurotoxin AuIB: A molecular dynamics simulation study.

AuIB, a neurotoxic conopeptide, is a "selective antagonist" of the α3-ß4 subtype of the nicotinic acetylcholine receptors in human brain and is investigated extensively for its immense potency in the treatment of pain. It contains two disulfide linkages, which are decisive in maintaining its structure and functional selectivity. Here we report, a molecular dynamics simulation study of the role of disulfide bonds on the secondary structure of AuIB in water. The native form of AuIB (N) is found to be significantly stable in water with very robust 310 and α-helical domains, featuring ∼47% of the total structure. The partially reduced AuIB (P2-8 ), with the disulfide bond between cysteine 2, 8 broken, shows significantly perturbed secondary structural features with almost total loss in helicity. Breaking of the disulfide bond between cysteine 3, 15 (P3-15 ), on the other hand, has almost no effect on the helical region of the peptide, although the weightage of ß-turn increased at the cost of random coil. Intriguingly, when both the disulfide bonds are broken (D), the helical region is affected, but the loss in helicity is less than that observed in the P2-8 case. To understand the disulfide scrambling process, the relative probabilities of forming three disulfide-bond isoforms of AuIB in water are estimated from the sulfur-sulfur (SS) distance distributions of the four cysteine residues present in AuIB (D). Simulations show that the native globular form dominates ∼73% of the isoform population, with the beads form being the second most populated one. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 196-209, 2016.

Simulations of solvation and solvation dynamics in an idealized ionic liquid model.

Equilibrium and nonequilibrium molecular dynamics simulations of solvation and solvation dynamics of a variety of solutes have been performed in the coarse-grained ionic liquid model ILM2 (Roy, D.; Maroncelli, M. J. Phys. Chem. B 2010, 114, 12629). Some comparisons are made between ionic and dipolar solvation using parallel simulations in CH(3)CN. Despite the fact that the multipolar character of electrostatic interactions and their spatial extent differ in the two solvents, solvation energies are equal to within about 10% in ILM2 and CH(3)CN. This near equality also holds with reduced accuracy in the case of reorganization energies. Solvation energies of spherical solutes in ILM2 and its variants can be correlated as a function of solute and solvent size using a Born-type expression with an effective cavity size. Solvation time correlation functions in ILM2 exhibit a subpicosecond inertial component followed by a broadly distributed component related to solvent viscosity, comparable to what has been observed in experiment. Direct comparison of simulation to experiment using the solute coumarin 153 (C153) shows general agreement on the time scales and character of the fast and slow components, but the amplitude of the fast component is overestimated by the simulations. Solute motion can significantly increase the speed of solvation, even in the case of large solutes such as C153. Good agreement is found between linear response estimates and the nonequilibrium dynamics associated with electronic excitation of C153. In contrast, perturbations involving changes of a full electron charge in atomic solutes lead to local heating which greatly hastens solvation compared to linear response predictions. The mechanism of charge solvation in atomic solutes is examined in some detail. It is found that ion translation dominates the inertial dynamics. The rotational contribution only becomes comparable to the translation contribution in the tail of the response. Adjustments of ion positions over distances of ~30% of their diameters are all that is required to relax the solvation energy in these systems.

Measurements of the complete solvation response of coumarin 153 in ionic liquids and the accuracy of simple dielectric continuum predictions.

The complete solvation response of coumarin 153 (C153) has been determined over the range 10(-13)-10(-8) s in a variety of ionic liquids by combining femtosecond broad-band fluorescence upconversion and picosecond time-correlated single photon counting measurements. These data are used together with recently reported dielectric data in eight ionic liquids to test the accuracy of a simple continuum model for predicting solvation dynamics. In most cases the features of the solvation response functions predicted by the dielectric continuum model are similar to the measured dynamics of C153. The predicted dynamics are, however, systematically faster than those observed, on average by a factor of 3-5. Computer simulations of a model solute/ionic liquid system also exhibit the same relationship between dielectric predictions and observed dynamics. The simulations point to spatial dispersion of the polarization response as an important contributor to the over-prediction of solvation rates in ionic liquids.