EGCG attenuates α-synuclein protofibril-membrane interactions and disrupts the protofibril

The fibrillary aggregates of a-synuclein (a-syn) are closely associated with the etiology of Parkinson's disease (PD). Mounting evidence shows that the interaction of a-syn with biological membranes is a culprit for its aggregation and cytotoxicity. While some small molecules can effectively inhibit a-syn fibrillization in solution, their potential roles in the presence of membrane are rarely studied. Among them, green tea extract epigallocatechin gallate (EGCG) is currently under active investigation. Herein, we investigated the effects of EGCG on a-syn protofibril (an intermediate of a-syn fibril formation) in the presence of a model membrane and on the interactions between a-syn protofibril and the membrane, as well as the underlying mechanisms, by performing microsecond all-atom molecular dynamics simulations. The results show that EGCG has destabilization effects on a-syn protofibril, albeit to a lesser extent than that in solution. Intriguingly, we find that EGCG forms overwhelming H-bonding and cation-p interactions with membrane and thus attenuates protofibril-membrane interactions. Moreover, the decreased protofibril-membrane interactions impede the membrane damage by a-syn protofibril and enable the membrane integrity. These findings provide atomistic understanding towards the attenuation of a-syn protofibril-induced cytotoxicity by EGCG in cellular environment, which is helpful for the development of EGCG-based therapeutic strategies against PD.