Microscopic Understanding of the Conformational Stability of the Aggregated Nonamyloid ß Components of α-Synuclein.

ABSTRACT

Self-association of α-synuclein peptides into oligomeric species and ordered amyloid fibrils is associated with Parkinson's disease, a progressive neurodegenerative disorder. In particular, the peptide domain formed between the residues Glu-61 (or E61) and Val-95 (or V95) of α-synuclein, typically termed the "nonamyloid ß component" (NAC), is known to play critical roles in forming aggregated structures. In this work, we have employed molecular dynamics simulations to explore the conformational properties and relative stabilities of aggregated protofilaments of different orders, namely, tetramer (P(4)), hexamer (P(6)), octamer (P(8)), decamer (P(10)), dodecamer (P(12)), and tetradecamer (P(14)), formed by the NAC domains of α-synuclein. Besides, center-of-mass pulling and umbrella sampling simulation methods have also been employed to characterize the mechanistic pathway of peptide association/dissociation and the corresponding free energy profiles. Structural analysis showed that the disordered C-terminal loop and the central core regions of the peptide units lead to more flexible and distorted structures of the lower order protofilaments (P(4) and P(6)) as compared to the higher order ones. Interestingly, our calculation shows the presence of multiple distinctly populated conformational states for the lower order protofilament P(4), which may drive the oligomerization process along multiple pathways to form different polymorphic α-synuclein fibrillar structures. It is further observed that the nonpolar interaction between the peptides and the corresponding nonpolar solvation free energy play a dominant role in stabilizing the aggregated protofilaments. Importantly, our result showed that reduced cooperativity during the binding of a peptide unit beyond a critical size of the protofilament (P(12)) leads to less favorable binding free energy of a peptide.