Importance of Solvent in Guiding the Conformational Properties of an Intrinsically Disordered Peptide

Abstract

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.

Dynamic Heterogeneity at the Interface of an Intrinsically Disordered Peptide

“…In an earlier report, 36 we studied in detail the locally heterogeneous conformational motions of the repeat units (R1 to R7) of α-synuclein peptide and their influence on the structural organization of water at the interface. The calculations averaged over an ensemble of different peptide conformations demonstrated comparatively greater rigidity of the biologically important R6 segment as against the other repeat unit segments.…”

“…34,40 Further details of the initial system setup can be found elsewhere. 36 We have used the conjugate-gradient minimization tool available in the NAMD code 37 to remove any initial stress present in the systems. On systematic raising of the temperature to 300 K, each system was equilibrated for a 10 ns duration under isothermal−isobaric ensemble (NPT) conditions.…”

“…The relatively slower relaxation of F tr (k, t) for water hydrating R6 with a 25−40% higher ⟨τ tr ⟩ value as compared to water solvating the other repeat units as observed is attributed to the greater conformational rigidity of R6, as reported earlier. 36 In Figure 6(a), we present the relaxation patterns of the rotational ISF (F rot (k, t)), defined as…”

“…Recently, we reported MD simulation results on the local conformational features of α-synuclein peptide in its monomeric state and the distribution of solvent (water) around those. 36 Most of the studies reported on IDPs, in general, and αsynuclein, in particular, are primarily focused on exploring the aggregation process under different conditions. However, molecular level understanding of the dynamical features of a hydrated IDP in its monomeric state has largely been unexplored.…”

“…Importantly, the solvent (water) present near the NAC region has been found to exhibit longer residence time. Recently, we reported MD simulation results on the local conformational features of α-synuclein peptide in its monomeric state and the distribution of solvent (water) around those …”