Dimerization of α-Synuclein Fragments Studied by Isothermal-Isobaric Replica-Permutation Molecular Dynamics Simulation.

Aggregates and fibrils of intrinsically disordered α-synuclein are associated with Parkinson's disease. Within a non-amyloid β component (NAC) spanning from the 61st to the 95th residue of α-synuclein, an 11-residue segment called NACore (GAVVTGVTAVA) is an essential region for both fibril formation and cytotoxicity. Although NACore peptides alone are known to form aggregates and amyloid fibrils, the mechanisms of aggregation and fibrillation remain unknown. This study investigated the dimerization process of NACore peptides as the initial stage of the aggregation and fibrillation processes. We performed an isothermal-isobaric replica-permutation molecular dynamics simulation, which is one of the efficient sampling methods, for the two NACore peptides in explicit water over 96 μs. The simulation succeeded in sampling a variety of dimer structures. An analysis of secondary structure revealed that most of the NACore dimers form intermolecular β-bridges. In particular, more antiparallel β-bridges were observed than parallel β-bridges. We also found that intramolecular secondary structures such as α-helix and antiparallel β-bridge are stabilized in the pre-dimer state. However, we identified that the intermolecular β-bridges tend to form directly between residues with no specific structure rather than via the intramolecular β-bridges. This is because the NACore peptides still have a low propensity to form the intramolecular secondary structures even though they are stabilized in the pre-dimer state.