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Dimerization of α-Synuclein Fragments Studied by Isothermal-Isobaric Replica-Permutation Molecular Dynamics
Masataka Yamauchi1,2,3, Hisashi Okumura1,2,3
1Department of Structural Molecular Science, The Graduate University for Advanced Studies(SOKENDAI), Okazaki, Aichi 444-8787, Japan.
Journal of Chemical Information and Modeling
|February 24, 2021
Summary
This study reveals how NACore peptides, crucial for Parkinson's disease-associated α-synuclein aggregation, form dimers. Molecular dynamics simulations show these dimers primarily adopt antiparallel β-bridges, initiating the fibrillation process.
Area of Science:
- Biochemistry
- Neuroscience
- Computational Biology
Background:
- Intrinsically disordered α-synuclein aggregates and fibrils are linked to Parkinson's disease.
- The NACore segment (residues 68-78) of α-synuclein is essential for fibril formation and cytotoxicity.
- Mechanisms underlying NACore peptide aggregation and fibrillation remain poorly understood.
Purpose of the Study:
- To investigate the dimerization process of NACore peptides as the initial step in aggregation and fibrillation.
- To elucidate the structural characteristics of NACore dimers and their role in initiating fibril formation.
Main Methods:
- Utilized isothermal-isobaric replica-permutation molecular dynamics simulations.
- Simulated two NACore peptides in explicit water for 96 microseconds.
- Analyzed secondary structures and dimer interfaces.
Main Results:
- Successfully sampled diverse dimer structures of NACore peptides.
- Identified that most NACore dimers form intermolecular β-bridges, predominantly antiparallel.
- Observed stabilization of intramolecular structures (α-helix, antiparallel β-bridge) in pre-dimer states.
- Found direct formation of intermolecular β-bridges from unstructured residues, bypassing intramolecular structures.
Conclusions:
- NACore peptide dimerization, primarily through antiparallel β-bridges, is a key initial event in α-synuclein aggregation.
- The direct formation of intermolecular β-bridges suggests a distinct aggregation pathway for NACore peptides.
- Understanding these early dimerization events provides insights into Parkinson's disease pathogenesis.
