Effects of Protein Conformational Flexibilities and Electrostatic Interactions on the Low-Frequency Vibrational Spectrum of Hydration Water

The conformational flexibility of a protein and its ability to form hydrogen bonds with water are expected to influence the microscopic properties of water layer hydrating the protein. Detailed molecular dynamics simulations with an aqueous solution of the globular protein barstar have been carried out to explore such influence on the low-frequency vibrational spectrum of the hydration water molecules. The calculations reveal that enhanced degree of confinement at the protein surface on freezing its local motions leads to increasingly restricted oscillatory motions of the hydration water molecules as evident from larger blue shifts of the corresponding band. Interestingly, conformational fluctuations of the protein and electrostatic component of its interaction with the solvent have been found to affect the transverse and longitudinal oscillations of hydration water molecules in a nonuniform manner. It is further noticed that the distributions of the low-frequency modes for the water molecules hydrogen bonded to the residues of different segments of the protein are heterogeneously altered. The effect is more around the frozen protein matrix and agrees well with slower protein–water hydrogen bond relaxations

Exploring the Dynamic Heterogeneity at the Interface of a Protein in Aqueous Ionic Liquid Solutions

Room temperature molecular dynamics (MD) simulations of the globular protein α-lactalbumin in aqueous solutions containing BMIM (1-butyl-3-methylimidazolium) based ionic liquids (ILs) with a series of Hofmeister anions have been carried out. In particular, effects of anions of different shapes/sizes and hydrophobic/hydrophilic characters, namely, thiocyanate (SCN–), dicyanamide (DCA–), methyl sulfate (MS–), triflate (TFO–), and bis(trifluoromethane) sulfonimide (TF2N–) on the heterogeneous dynamic environment at the interface around the protein have been explored. The calculations revealed exchange of population between water and IL cation–anion components beyond the first layer of bound water molecules at the protein surface. Further, increasingly restricted diffusivity of the IL components and water around the protein has been found to be associated with a longer time scale for the onset of dynamic heterogeneity at the interface. Restricted diffusivity of water molecules at the interface in the presence of the ILs has been found to be correlated with the longer time scale of structural relaxations of protein–water hydrogen bonds at the interface. More importantly, the time scale associated with the reorientations of the anions has been found to be anticorrelated with their translational diffusivity, with the effect being more at the interface as compared to the bulk IL solutions. It is demonstrated that the nonuniform ability of the anions to form hydrogen bonds with water due to their differential shapes and hydrophilic characters is the origin of such anticorrelation

Size-Dependent Conformational Features of Aβ_17–42 Protofilaments from Molecular Simulation Studies

Alzheimer’s disease is caused due to aggregation of amyloid beta (Aβ) peptide into soluble oligomers and insoluble fibrils in the brain. In this study, we have performed room temperature molecular dynamics simulations to probe the size-dependent conformational features and thermodynamic stabilities of five Aβ_17–42 protofilaments, namely, O₅ (pentamer), O₈ (octamer), O₁₀ (decamer), O₁₂ (dodecamer), and O₁₄ (tetradecamer). Analysis of the free energy profiles of the aggregates showed that the higher order protofilaments (O₁₀, O₁₂, and O₁₄) undergo conformational transitions between two minimum energy states separated by small energy barriers, while the smaller aggregates (O₅ and O₈) remain in single deep minima surrounded by high barriers. Importantly, it is demonstrated that O₁₀ is the crossover point for which the twisting of the protofilament is maximum, beyond which the monomers tend to rearrange themselves in an intermediate state and eventually transform into more stable conformations. Our results suggest that the addition of monomers along the axis of an existing protofilament with a critical size (O₁₀ according to the present study) proceeds via an intermediate step with relatively less stable twisted structure that allows the additional monomers to bind and form stable larger protofilaments with minor rearrangements among themselves. More importantly, it is demonstrated that a combination of twist angle and end-to-end distance can be used as a suitable reaction coordinate to describe the growth mechanism of Aβ protofilaments in simulation studies

Hydration Behavior along the Folding Pathways of Trpzip4, Trpzip5 and Trpzip6

The microscopic properties of water confined within different segments of Trpzip4 (TZ4), Trpzip5 (TZ5), and Trzpip6 (TZ6) have been compared for all the states characterized along their folding pathways. In particular, structural ordering, energetics, and dynamics of water have been examined as the peptide unfolds along the free energy landscape. It is observed that the structuring of tetrahedral network as well as translational and rotational motions of hydration waters confined within the strands and the turn regions are very different, revealing motional heterogeneity in small 16-residue trpzips. The polar and charged groups present at the peptide surface anchor to water molecules through hydrogen bonds and are responsible for differential hydration among various segments of the peptide, which is found to be correlated to their hydropathy values. The coherent collective dynamics of water is strongly coupled with conformational changes in the peptide since the trends observed in most of the computed quantities are in accordance with the folded and unfolded states classified along the folding pathway for all trpzips. The hydration behavior conform to the heterogeneity observed in the free energy landscape of stable TZ4 with four unfolded states as compared to more flexible TZ5 and TZ6 with two unfolded states each, in addition to the folded state. The hydration waters are observed to regulate the protein dynamics by continuous fluctuations in hydrogen bond network involving lateral side chains that inject conformational motions in the peptide to facilitate its unfolding. The implications of mutations on various aspects of hydration water dynamics including their impact on structural and dynamic organization of hydrogen bonds are also highlighted. Our studies affirm that topology of the free energy landscape is shaped by both spatial organization and dynamic transitions in hydration waters in addition to the conformational fluctuations in the peptide along the folding pathway

Impact of an Ionic Liquid on Amino Acid Side Chains: A Perspective from Molecular Simulation Studies

Ionic liquids (ILs) are known to modify the structural stability of proteins. The modification of the protein conformation is associated with the accumulation of ILs around the amino acid (AA) side chains and the nature of interactions between them. To understand the microscopic picture of the structural arrangements of ILs around the AA side chains, room temperature molecular dynamics (MD) simulations have been carried out in this work with a series of hydrophobic, polar and charged AAs in aqueous solutions containing the IL 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]) at 2 M concentration. The calculations revealed distinctly nonuniform distribution of the IL components around different AAs. In particular, it is demonstrated that the BMIM+ cations preferentially interact with the aromatic AAs through favorable stacking interactions between the cation imidazolium head groups and the aromatic AA side chains. This results in preferential parallel alignments and enhanced population of the cations around the aromatic AAs. The potential of mean force (PMF) calculations revealed that such favorable stacking interactions provide greater stability to the contact pairs (CPs) formed between the aromatic AAs and the IL cations as compared to the other AAs. It is further quantified that for most of the AAs (except the cationic ones), a favorable enthalpy contribution more than compensates for the entropy cost to form stable CPs with the IL cations. These findings are likely to provide valuable fundamental information toward understanding the effects of ILs on protein conformational stability