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

Authors : Moutusi Manna* and Rajesh K. Murarka*



-Synuclein is an intrinsically disordered protein, whose aggregation into amyloid fibril is involved in the pathology of Parkinson’s disease. C-terminally truncated -synuclein variants, which are naturally generated from the full-length   -synuclein, are enriched in the pathological  -synuclein aggregates and known to significantly enhance the aggregation process. In this work, we have performed extensive Gaussian accelerated molecular dynamics simulations (3.8 s in total) to characterize the equilibrium conformational ensemble of a physiologically relevant C-terminally truncated -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 -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 -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 -synuclein in vivo.



-Synuclein, C-terminal truncation, conformational ensemble, free-energy landscape, molecular dynamics simulations, enhanced sampling.