The Zika virus (ZIKV) was responsible for a recent debilitating epidemic that till date has no cure. A potential way to reduce ZIKV virulence is to limit the action of the non-structural proteins involved in its viral replication. One such protein, NS1, encoded as a monomer by the viral genome, plays a major role via symmetric oligomerization. We examine the homodimeric structure of the dominant b-ladder segment of NS1 with extensive all atom molecular dynamics. We find it stably bounded by two spatially separated interaction clusters (C1 and C2) with significant differences in the nature of their interactions. Four pairs of distal, intramonomeric disulfide bonds are found to be coupled to the stability, local structure, and wettability of the interfacial region. Symmetric reduction of the intra-monomeric disulfides triggers marked dynamical heterogeneity, interfacial wettability and asymmetric salt bridging propensity. Harnessing the model-free Lipari-Szabo based formalism for estimation of conformational entropy (S conf ), we find clear signatures of heterogeneity in the monomeric conformational entropies. The observed asymmetry, very small in the unperturbed state, expands significantly in the reduced states. This allosteric effect is most noticeable in the electrostatically bound C2 cluster that underlies the greatest stability in the unperturbed state.Allosteric induction of conformational and thermodynamic asymmetry is expected to affect the pathways leading to symmetric higher ordered oligomerization, and thereby affect crucial replication pathways.
The effect of extreme temperature on amyloidogenic species remains sparsely explored. In a recent study (J. Phys. Chem. Lett., 2019, 10, (10)), we employed exhaustive molecular dynamics simulations to explore the cold thermal response of a putative small amyloid oligomer and to elicit the role of solvent modulation. Herein, we investigate the dynamical response of the hydration waters of the oligomer within the supercooled states. Using NMR-based formalism, we delineate the entropic response in terms of the side-chain conformational entropy that corroborates the weakening of the hydrophobic core with lowering of temperature. The translational dynamics of the protein and hydration waters reveal the coupling of protein dynamical fluctuations with solvent dynamics under supercooled conditions. Probing the translational motion as a space–time correlation indicates glassy dynamics exhibited by hydration waters in the supercooled regime. Caging of the water molecules with lowering of temperature and the resultant hopping dynamics are reflected in the longer β-relaxation timescales of translational motion. Furthermore, we utilized mode-coupling theory (MCT) and derived the ideal glass transition temperature from translational and rotational dynamics, around ∼196 and 209 K, respectively. Interestingly, rotational motion in the supercooled regime deviates from the MCT law, exhibits Arrhenius motion, and marks a fragile-to-strong crossover at 227 K. The low-frequency vibrational modes also coincide with the dynamical transition. This exposition lends dynamical insights into the hydration coupling of an amyloid aggregate under cryogenic conditions.
The co-involvement of biological molecules and nanomaterials has increasingly come to the fore in modern-day applications. While the “bio–nano” (BN) interface presents physico-chemical characteristics that are manifestly different from those observed in isotropic bulk conditions, the underlying molecular reasons remain little understood; this is especially true of anomalies in interfacial hydration. In this paper, we leverage atomistic simulations to study differential adsorption characteristics of a small protein on the inner (concave) surface of a single-walled carbon nanotube whose diameter exceeds dimensions conducive to single-file water movement. Our findings indicate that the extent of adsorption is decided by the degree of foldedness of the protein conformational substate. Importantly, we find that partially folded substates, but not the natively folded one, induce reorganization of the protein hydration layer into an inner layer water closer to the nanotube axis and an outer layer water in the interstitial space near the nanotube walls. Further analyses reveal sharp dynamical differences between water molecules in the two layers as observed in the onset of increased heterogeneity in rotational relaxation and the enhanced deviation from Fickian behavior. The vibrational density of states reveals that the dynamical distinctions are correlated with differences in crucial bands in the power spectra. The current results set the stage for further systematic studies of various BN interfaces vis-à-vis control of hydration properties.
The advent of nanotechnology has seen a growing interest in the nature of fluid flow and transport under nanoconfinement. The present study leverages fully atomistic molecular dynamics (MD) simulations to study the effect of nanochannel length and intrusion of molecules of the organic solvent, hexafluoro-2-propanol (HFIP), on the dynamical characteristics of water within it. Favorable interactions of HFIP with the nanochannels comprised of single-walled carbon nanotubes traps them over time scales greater than 100 ns, and confinement confers small but distinguishable spatial redistribution between neighboring HFIP pairs. Water molecules within the nanochannels show clear signatures of dynamical slowdown relative to bulk water even for pure systems. The presence of HFIP causes further rotational and translational slowdown in waters when the nanochannel dimension falls below a critical length of 30 Å. The enhanced slowdown in the presence of HFIP is quantified from characteristic relaxation parameters and diffusion coefficients in the absence and presence of HFIP. It is finally seen that the net flow of water between the ends of the nanochannel shows a decreasing dependence with nanochannel length only when the number of HFIP molecules is small. These results lend insights into devising ways of modulating solvent properties within nanochannels with cosolvent impurities.
Amyloid fibril formation of proteins is of great concern in neurodegenerative disease and can be detrimental to the storage and stability of biologics. Recent evidence suggests that insulin fibril formation reduces the efficacy of type II diabetes management and may lead to several complications. To develop anti-amyloidogenic compounds of endogenous origin, we have utilized the hydrogen bond anchoring, π stacking ability of porphyrin, and investigated its role on the inhibition of insulin amyloid formation. We report that hydroxylation and metal removal from the heme moiety yields an excellent inhibitor of insulin fibril formation.Thioflavin T, tyrosine fluorescence, Circular Dichorism (CD) spectroscopy, Field emission scanning electron microscopy (FESEM) and molecular dynamics (MD) simulation studies suggest that hematoporphyrin (HP) having hydrogen bonding ability on both sides is a superior inhibitor compared to hemin and protoporphyrin (PP). Experiments with hen egg white lysozyme (HEWL) amyloid fibril formation also validated the efficacy of endogenous porphyrin based small molecules. Our results will help to decipher a general therapeutic strategy to counter amyloidogenesis.
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