Unravelling the destabilization potential of ellagic acid on α-synuclein fibrils using molecular dynamics simulations

The aberrant deposition of α-synuclein (α-Syn) protein into the intracellular neuronal aggregates termed Lewy bodies and Lewy neurites characterizes the devastating neurodegenerative condition known as Parkinson's disease (PD). The disruption of pre-existing disease-relevant α-Syn fibrils is recognized as a viable therapeutic approach for PD. Ellagic acid (EA), a natural polyphenolic compound, is experimentally proven as a potential candidate that prevents or reverses the α-Syn fibrillization process. However, the detailed inhibitory mechanism of EA against the destabilization of α-Syn fibril remains largely unclear. In this work, the influence of EA on α-Syn fibril and its putative binding mechanism were explored using molecular dynamics (MD) simulations. EA interacted primarily with the non-amyloid-β component (NAC) of α-Syn fibril, disrupting its β-sheet content and thereby increasing the coil content. The E46-K80 salt bridge, critical for the stability of Greek-key-like α-Syn fibril, was disrupted in the presence of EA. The binding free energy analysis using the MM-PBSA method demonstrates the favourable binding of EA to α-Syn fibril (ΔG_binding = -34.62 ± 11.33 kcal mol^-1). Interestingly, the binding affinity between chains H and J of the α-Syn fibril was significantly reduced on the incorporation of EA, which highlights the disruptive ability of EA towards α-Syn fibril. The MD simulations provide mechanistic insights into the α-Syn fibril disruption by EA, which gives a valuable direction for the development of potential inhibitors of α-Syn fibrillization and its associated cytotoxicity.