Exploring the Impact of Physiological C‑Terminal\nTruncation on α‑Synuclein Conformations to Unveil Mechanisms\nRegulating Pathological Aggregation

Emerging\nevidence suggests that physiological C-terminal truncation\nof α-synuclein (αS) plays a critical role in regulating\nliquid–liquid phase separation and promoting amyloid aggregation,\nprocesses implicated in neurodegenerative diseases such as Parkinson’s\ndisease (PD). However, the molecular mechanisms through which C-terminal\ntruncation influences αS conformation and modulates its aggregation\nremain poorly understood. In this study, we investigated the impact\nof C-terminal truncation on αS conformational dynamics by comparing\nfull-length αS<sub>1–140</sub> with truncated αS<sub>1–103</sub> monomers using atomistic discrete molecular dynamics\nsimulations. Our findings revealed that both αS<sub>1–140</sub> and αS<sub>1–103</sub> primarily adopted helical conformations\naround residues 7–32, while residues 36–95, located\nin the second half of the N-terminal and NAC domains, predominantly\nformed a dynamic β-sheet core. The C-terminus of αS<sub>1–140</sub> was largely unstructured and dynamically wrapped\naround the β-sheet core. While residues 1–95 exhibited\nsimilar secondary structure propensities in both αS<sub>1–140</sub> and αS<sub>1–103</sub>, the dynamic capping by the\nC-terminus in αS<sub>1–140</sub> slightly enhanced β-sheet\nformation around residues 36–95. In contrast, key aggregation-driving\nregions (residues 2–9, 36–42, 45–57, and 68–78)\nwere dynamically shielded by the C-terminus in αS<sub>1–140</sub>, reducing their exposure and potentially preventing interpeptide\ninteractions that drive aggregation. C-terminal truncation, on the\nother hand, increased the exposed surface area of these aggregation-prone\nregions, thereby enhancing interpeptide interactions, phase separation,\nand amyloid aggregation. Overall, our simulations provide valuable\ninsights into the conformational effects of C-terminal truncation\non αS and its role in promoting pathological aggregation.