Characterization of conformational ensemble of C-terminally truncated α-synuclein in aqueous solution by atomistic molecular dynamics simulations

Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhopal-462 066, Madhya Pradesh, India E-mail: moutusi.manna.chem@gmail.com, rkm@iiserb.ac.in Manuscript received online 30 April 2019, revised and accepted 28 May 2019 α-Synuclein is an intrinsically disordered protein, whose aggregation into amyloid fibril is involved in the pathology of Parkinson’s disease. C-terminally truncated α-synuclein variants, which are naturally generated from the full-length α-synuclein, are enriched in the pathological α-synuclein aggregates and known to significantly enhance the aggregation process. In this work, we have performed extensive Gaussian accelerated molecular dynamics simulations (3.8 µs in total) to characterize the equilibrium conformational ensemble of a physiologically relevant C-terminally truncated α-synuclein monomer, AS(1-103), in aqueous solution. The nearly flat free-energy landscape of AS(1-103) suggests coexistence of multiple distinct conformational states, including disordered conformations and conformations with transient secondary and tertiary structures. We found that the predominant conformation of AS(1-103) in aqueous solution exhibit enrichment of β-sheet structure at different parts of the N-terminal and hydrophobic NAC domain, including the aggregation-prone NAC-core. We identified moderate intra- and inter-domain interactions within the N-terminal and the NAC domain that enhance and stabilize the partially folded β-sheet rich structures of AS(1-103) in solution. Such stable structural regions formed in the AS(1-103) ensemble, may serve as potential molecular signature that encodes the aggregation seed. The presented work enables characterization of conformational states of monomeric AS(1-103) in solution, and provide a plausible explanation for the experimentally determined enhanced aggregation propensity of C-terminally truncated variants of α-synuclein in vivo