Misfolding of α-synuclein monomers gives rise to toxic oligomers and fibrils that accumulate as Lewy bodies, a hallmark of Parkinson’s disease. Recently, Hilt et al. found a series of paramagnetic amyloid ligands (PALs) as small-molecule inhibitors targetingα-synuclein. PALs share a two-ring aromatic scaffold and a nitroxide group: the rigid aromatics promote π-π stacking with α-synuclein, while the nitroxide enhances detectability by NMR and scavenges reactive oxygen species. Unfortunately, the molecular binding mechanisms behind PAL to α-synuclein remain unclear, largely due to the experimental challenges on studying IDPs structure for their rapidly changing conformations. Experimental techniques often cannot simultaneously capture atomic-resolution structural details and dynamic information without sacrifice the other. Molecular dynamics (MD) simulations therefore become a powerful tool to study ligand binding mechanism for being able to capture atomic-resolution structural details and dynamic information in the same time. Here, we employ ligand Gaussian accelerated molecular dynamics (LiGaMD) to resolve the binding modes of several PALs and their effects on α-synuclein conformational ensembles. We find that PAL-1202 biases theα-synuclein monomer toward a more compact state that protects intramolecular hydrogen bonds from solvent disruption. Consistent with stabilization of a nontoxic native-like ensemble, PAL-901 and PAL-1202 increase “Contact A,” a previously reported intramolecular contact associated with reduced aggregation propensity. We further identify residue 94 as a critical interaction hotspot: mutation at this position markedly alters the conformational response. Notably, only PAL-1202 brings neighboring residues 95–97 among the top contacts, indicating additional engagement of the C-terminal region that may help shield the aggregation-prone NAC segment and thereby suppress oligomerization. Together, these results provide atomistic insight into how PALs reshape α-synuclein conformational distribution, highlighting residue-specific interactions that could guide the design of next-generation anti-aggregation ligands.
Hung-Yu Wan (Sun,) studied this question.