In silico study on graphene quantum dots modified with various functional groups inhibiting α‑synuclein dimerization

Hypothesis: Graphene quantum dots (GQDs) with various functional groups are hypothesized to inhibit the α-synuclein (αS) dimerization, a crucial step in Parkinson's disease pathogenesis. The potential of differently functionalized GQDs is systematically explored. Experiments: All-atom replica-exchange molecular dynamics simulations (accumulating to 75.6 μs) in explicit water were performed to study the dimerization of the αS non-amyloid component region and the influence of GQDs modified with various functional groups. Conformation ensemble, binding behavior, and free energy analysis were conducted. Findings: All studied GQDs inhibit β-sheet and backbone hydrogen bond formation in αS dimers, leading to looser oligomeric conformations. Charged GQDs severely impede the growth of extended β-sheets by providing extra contact surface. GQD binding primarily disrupts αS inter-peptide interactions through π-π stacking, CH-π interactions, and for charged GQDs, additionally through salt-bridge and hydrogen bonding interactions. GQD-COO– showed the most optimal inhibitory effect, binding mode, and intensity, which holds promise for the development of nanomedicines targeting amyloid aggregation in neurodegenerative diseases.