Abstract
The role of alpha-synuclein (αS) amyloid fibrillation has been recognized in various neurological diseases including Parkinson’s Disease (PD). In early stages, fibrillation occurs by the structural transition from helix to extended states in monomeric αS followed by the formation of beta-sheets. This alpha-helix to beta-sheet transition (αβT) speeds up the formation of amyloid fibrils through the formation of unstable and temporary configurations of the αS. In this study, the most important regions that act as initiating nuclei and make unstable the initial configuration were identified based on sequence and structural information. In this regard, a Targeted Molecular Dynamics (TMD) simulation was employed using explicit solvent models under physiological conditions. Identified regions are those that are in the early steps of structural opening. The trajectory was clustered the structures characterized the intermediate states. The findings of this study would help us to better understanding of the mechanism of amyloid fibril formation.
Highlights
The role of alpha-synuclein amyloid fibrillation has been recognized in various neurological diseases including Parkinson’s Disease (PD)
Aggregation of proteins into amyloid fibrils is associated with many neurological diseases such as Alzheimer’s disease (AD)[1], Parkinson’s disease (PD)[2], and Type-2 Diabetes (T2D)[3]
Many therapeutic approaches of PD are based on the prevention of amyloid fibrillation or destabilization of pre-existing fibrils[9,10]
Summary
The role of alpha-synuclein (αS) amyloid fibrillation has been recognized in various neurological diseases including Parkinson’s Disease (PD). Fibrillation occurs by the structural transition from helix to extended states in monomeric αS followed by the formation of beta-sheets. This alpha-helix to beta-sheet transition (αβT) speeds up the formation of amyloid fibrils through the formation of unstable and temporary configurations of the αS. The most important regions that act as initiating nuclei and make unstable the initial configuration were identified based on sequence and structural information In this regard, a Targeted Molecular Dynamics (TMD) simulation was employed using explicit solvent models under physiological conditions. Stages of the αS fibrillation process, a conformational transition occurs from helical to extended structures followed by the creation of beta-sheets, and eventually forming of amyloid fibrils[22]. Critical sites of αS influencing on β-formation at early stages can be identified by focusing on the α-β conformational transition (αβT)
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