Aggregated form of α-synuclein in the brain has been found to be the major component of Lewy bodies that are hallmarks of Parkinson′s disease (PD), the second most devastating neurodegenerative disorder. We have carried out room-temperature all-atom molecular dynamics (MD) simulations of an ensemble of widely different α-synuclein1–95 peptide monomer conformations in aqueous solution. Attempts have been made to obtain a generic understanding of the local conformational motions of different repeat unit segments, namely R1–R7, of the peptide and the correlated properties of the solvent at the interface. The analyses revealed relatively greater rigidity of the hydrophobic R6 unit as compared to the other repeat units of the peptide. Besides, water molecules around R6 have been found to be less structured and weakly interacting with the peptide. These are important observations as the R6 unit with reduced conformational motions can act as the nucleation site for the aggregation process, while less structured weakly interacting water around it can become displaced easily, thereby facilitating the hydrophobic collapse of the peptide monomers and their association during the nucleation phase at higher concentrations. In addition, we demonstrated presence of doubly coordinated highly ordered as well as triply coordinated relatively disordered water molecules at the interface. We believe that while the ordered water molecules can favor water-mediated interactions between different peptide monomers, the randomly ordered ones on the other hand are likely to be expelled easily from the interface, thereby facilitating direct peptide–peptide interactions during the aggregation process.

It is believed that water around an intrinsically disordered protein or peptide (IDP) in an aqueous environment plays an important role in guiding its conformational properties and aggregation behavior. However, despite its importance, only a handful of studies exploring the correlation between the conformational motions of an IDP and the microscopic properties of water at its surface are reported. Attempts have been made in this work to study the dynamic properties of water present in the vicinity of α-synuclein, an IDP associated with Parkinson’s disease (PD). Room temperature molecular dynamics (MD) simulations of eight α-synuclein1–95 peptides with a wide range of initial conformations have been carried out in aqueous media. The calculations revealed that due to solid-like caging motions, the translational and rotational mobility of water molecules near the surfaces of the peptide repeat unit segments R1 to R7 are significantly restricted. A small degree of dynamic heterogeneity in the hydration environment around the repeat units has been observed with water near the hydrophobic R6 unit exhibiting relatively more restricted diffusivity. The time scales involving the overall structural relaxations of peptide–water and water–water hydrogen bonds near the peptide have been found to be correlated with the time scale of diffusion of the interfacial water molecules. We believe that the relatively more hindered dynamic environment near R6 can help create water-mediated contacts centered around R6 between peptide monomers at a higher concentration, thereby enhancing the early stages of peptide aggregation.

No abstract

Ionic liquids (ILs), depending on their cation–anion combinations, are known to influence the conformational properties and activities of proteins in a nonuniform manner. To obtain microscopic understanding of such influence, it is important to characterize protein–IL interactions and explore the modified solvation environment around the protein. In this work, molecular dynamics (MD) simulations of the globular protein α-lactalbumin have been carried out in aqueous IL solutions containing 1-butyl-3-methylimidazolium cations (BMIM+) in combination with a series of anions with varying degree of hydrophilicity, namely, hexafluorophosphate (PF6 –), ethyl sulfate (ETS–), acetate (OAc–), chloride (Cl–), dicyanamide (DCA–), and nitrate (NO3 –) . The calculations revealed that ILs with hydrophobic and hydrophilic anions have contrasting influence on conformational flexibility of the protein. It is further observed that the BMIM+ cations exhibit site-specific orientations at the interface depending on the hydrophilicity of the anion component. Most importantly, the results demonstrated enhanced propensity of hydrophilic ILs to replace relatively weaker protein–water hydrogen bonds by stronger protein–IL hydrogen bonds at the protein surface as compared to the hydrophobic ILs. Such breaking of protein–water hydrogen bonds at a greater extent leads to greater loss of water hydrating the protein in the presence of hydrophilic ILs, thereby reducing the protein’s stability.

No abstract