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J Biomol Struct Dyn. 2020 Feb 11:1-25. doi: 10.1080/07391102.2020.1728384. [Epub ahead of print]

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

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1
Molecular Modelling and Simulation Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur-784 028, Assam, India.

Abstract

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 non-toxic aggregates. Therefore, understanding the conformational dynamics of α-synuclein monomer in 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 MD trajectory analysis, we noticed that when OleA is bound to α-synuclein, the intramolecular distance between non-amyloid-β component (NAC) domain and C-terminal domain of α-synuclein was increased, while long-range hydrophobic interactions between the two region was reduced. OleA 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 (BFE) 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 growth of stable and non-toxic aggregates.

KEYWORDS:

Parkinson’s disease; Protein aggregation; molecular dynamics; protein misfolding

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