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

The aberrant deposition of alpha-synuclein (alpha-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 alpha-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 alpha-Syn fibrillization process. However, the detailed inhibitory mechanism of EA against the destabilization of alpha-Syn fibril remains largely unclear. In this work, the influence of EA on alpha-Syn fibril and its putative binding mechanism were explored using molecular dynamics (MD) simulations. EA interacted primarily with the non-amyloid-beta component (NAC) of alpha-Syn fibril, disrupting its beta-sheet content and thereby increasing the coil content. The E46-K80 salt bridge, critical for the stability of Greek-key-like alpha-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 alpha-Syn fibril (Delta G(binding) = -34.62 +/- 11.33 kcal mol(-1)). Interestingly, the binding affinity between chains H and J of the alpha-Syn fibril was significantly reduced on the incorporation of EA, which highlights the disruptive ability of EA towards alpha-Syn fibril. The MD simulations provide mechanistic insights into the alpha-Syn fibril disruption by EA, which gives a valuable direction for the development of potential inhibitors of alpha-Syn fibrillization and its associated cytotoxicity.