Computational investigation on the conformational dynamics of C-terminal truncated α-synuclein bound to membrane

Accelerated progression rates in Parkinson's disease (PD) have been linked to C-terminal domain (CTD) truncations of monomeric α-Synuclein (α-Syn), which have been suggested to increase amyloid aggregation in vivo and in vitro. In the brain of PD patients, CTD truncated α-Syn was found to have lower cell viability and tends to increase in the formation of fibrils. The CTD of α-Syn acts as a guard for regulating the normal functioning of α-Syn. The absence of the CTD may allow the N-terminal of α-Syn to interact with the membrane thereby affecting the normal functioning of α-Syn, and all of which will affect the etiology of PD. In this study, the conformational dynamics of CTD truncated α-Syn (1-99 and 1-108) monomers and their effect on the protein-membrane interactions were demonstrated using the all-atom molecular dynamics (MD) simulation method. From the MD analyses, it was noticed that among the two truncated monomers, α-Syn (1-108) was found to be more stable, shows rigidness at the N-terminal region and contains a significant number of intermolecular hydrogen bonds between the non-amyloid β-component (NAC) region and membrane, and lesser number of extended strands. Further, the bending angle in the N-terminal domain was found to be lesser in the α-Syn (1-108) in comparison with the α-Syn (1-99). Our findings suggest that the truncation on the CTD of α-Syn affects its interaction with the membrane and subsequently has an impact on the aggregation.