Computational investigation on the effect of Oleuropein aglycone on the α-synuclein aggregation.

Parkinson's disease (PD) is considered to be the second most common progressive neurodegenerative brain disorder after Alzheimer's disease, which is caused by misfolding and aggregation of Alpha-synuclein (α-synuclein). It is characterized by distinct aggregated fibrillary form of α-synuclein known as the Lewy bodies and Lewy neurites. The most promising approach to combat PD is to prevent the misfolding and subsequent aggregation of α-synuclein. Recently, Oleuropein aglycone (OleA) has been reported to stabilize the monomeric structure of α-synuclein, subsequently favoring the growth of nontoxic aggregates. Therefore, understanding the conformational dynamics of α-synuclein monomer in the presence of OleA is significant. Here, we have investigated the effect of OleA on the conformational dynamics and the aggregation propensity of α-synuclein using molecular dynamics simulation. From molecular dynamics trajectory analysis, we noticed that when OleA is bound to α-synuclein, the intramolecular distance between non-amyloid-β component domain and C-terminal domain of α-synuclein was increased, whereas long-range hydrophobic interactions between the two region were reduced. Oleuropein aglycone was found to interact with the N-terminal domain of α-synuclein, making this region unavailable for interaction with membranes and lipids for the formation of cellular toxic aggregates. From the binding-free energy analysis, we found binding affinity between α-synuclein and OleA to be indeed high (ΔGbind = -12.56 kcal mol-1 from MM-PBSA and ΔGbind = -27.41 kcal mol-1from MM-GBSA). Our findings in this study thus substantiate the effect of OleA on the structure and stabilization of α-synuclein monomer that subsequently favors the growth of stable and nontoxic aggregates.Communicated by Ramaswamy H. Sarma.