Molecular Insights into the Misfolding and Dimerization Dynamics of the Full-Length α-Synuclein from Atomistic Discrete Molecular Dynamics Simulations

Abstract

The misfolding and pathological aggregation of α-synuclein forming insoluble amyloid deposits is associated with Parkinson’s disease, the second most common neurodegenerative disease in the world population. Characterizing the self-assembly mechanism of α-synuclein is critical for discovering treatments against synucleinopathies. The intrinsically disordered property, high degrees of freedom, and macroscopic timescales of conformational conversion make its characterization extremely challenging in vitro and in silico. Here, we systematically investigated the dynamics of monomer misfolding and dimerization of the full-length α-synuclein using atomistic discrete molecular dynamics simulations. Our results suggested that both α-synuclein monomers and dimers mainly adopted unstructured formations with partial helices around the N-terminus (residues 8–32) and various β-sheets spanning the residues 35–56 (N-terminal tail) and residues 61–95 (NAC region). The C-terminus mostly assumed an unstructured formation wrapping around the lateral surface and the elongation edge of the β-sheet core formed by an N-terminal tail and NAC regions. Dimerization enhanced the β-sheet formation along with a decrease in the unstructured content. The inter-peptide β-sheets were mainly formed by the N-terminal tail and NACore (residues 68–78) regions, suggesting that these two regions played critical roles in the amyloid aggregation of α-synuclein. Interactions of the C-terminus with the N-terminal tail and the NAC region were significantly suppressed in the α-synuclein dimer, indicating that the interaction of the C-terminus with the N-terminal tail and NAC regions could prevent α-synuclein aggregation. These results on the structural ensembles and early aggregation dynamics of α-synuclein will help understand the nucleation and fibrillization of α-synuclein.

Dissecting the Self-assembly Dynamics of Imperfect Repeats in α-Synuclein

“…5,6 There are no solution structures available in the PDB for the cytosolic form of αS. 17 Here, we only used the micellebound PDB structure of αS as the starting conformation for each repeat. These initially helical fragments rapidly converted to coils in our simulations (Figures S1 and S2), suggesting that our results were independent of the initial structures.…”

“…44,45 In addition, the accuracy of the Medusa force field with the EEF1 implicit solvation model in the aggregation of functional amyloid peptides of suckerin 46 and pathological amyloid polypeptides of hIAPP 26 has been benchmarked by the standard MD simulations with an explicit solvent model in our prior studies. With significantly enhanced sampling efficiency, the DMD algorithm has been widely used to study protein folding and amyloid aggregation, both by our group 17,25,26 and by others. 27,28,47 Analysis Methods.…”

“…Monomers of αS are natively disordered with transient long-range intradomain interactions, resulting in a smaller radius of gyration than expected for a fully unfolded 140-residue protein . Prior experimental and computational studies have shown that the long-range interactions drive αS monomers to form some metastable compact globular conformations. ,, Apart from the NAC domain, a portion of the N-terminal domain also participates in forming the cross-β core of αS fibrils . In the fibrillar form, αS adopts an in-register parallel β-sheet conformation with the β-sheet residues spanning 38–95, while the rest of the terminal residues likely assume unstructured conformations. ,− The truncation of the C-terminus enhances the aggregation rate of αS, suggesting that the presence of the C-terminal tail might protect against amyloid aggregation. , …”

SEVI Inhibits Aβ Amyloid Aggregation by Capping the β-Sheet Elongation Edges

“…39 To investigate the inhibition mechanism of SEVI against Aβ fibrillization, we systematically studied the interactions between Aβ42 and SEVI by applying multiple long-timescale discrete molecular dynamics (DMD) simulations. 51,52 DMD is a rapid and predictive MD algorithm widely used to study protein folding and misfolding by both our group 53,54 and others. 55−57 Our results revealed that SEVI was intrinsically disordered with dynamic formation of helixes and had a significantly weaker self-aggregation tendency compared to Aβ42.…”

Effect of Electric Field on α-Synuclein Fibrils: Revealed by Molecular Dynamics Simulations

“…MD simulations offer atomistic-level insights into individual amylogenic protein conformations and their aggregates. For instance, the full-length α-synuclein monomer and dimer were investigated by means of atomistic discrete MD simulations [ 44 ]. The modeling results predicted the formation of partial helices around the N-terminus (residues 8–32).…”