(88c) Elucidating the Binding Mechanism of Paramagnetic Amyloid Ligands to ?-Synuclein Monomer

It is well known that the hallmark of Parkinson’s disease (PD) is the accumulation of α-synuclein oligomers (αSOs), which is one of the aggregate forms of α-synuclein. Recently, our collaborator, Prof. John Voss (UC Davis), has found that paramagnetic amyloid ligands (PALs) could potentially inhibit the formation of αSOs. However, the specific mechanism of how PALs interact and block the aggregation is unknown, which is crucial for drug discovery for PD.

In this study, we utilized Ligand Gaussian accelerated Molecular Dynamics (LiGaMD) simulations to examine the interactions between PALs and the α-synuclein monomer. Our findings indicate that a 1μs LiGaMD is sufficient for our system, as evidenced by the near-zero auto-correlation values observed after the 1 μs run. Notably, we discovered that most PALs exhibit the highest molecular dynamics (MD) contact probability within the non-amyloid β component (NAC) region, which spans residues 61 to 94 of the α-synuclein monomer. This suggests that PALs are more likely to bind to the NAC region instead of the N-terminal or C-terminal regions of the α-synuclein monomer. Additionally, our results suggest that PALs may impede the formation of secondary structures, particularly α-helices and β-sheets. Moreover, to identify the most predominant structure within our system, we utilized k-means clustering analysis, which shows that there is not much difference between the bound and unbound states of the α-synuclein monomer.