4.7 Article

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

期刊

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 39, 期 4, 页码 1259-1270

出版社

TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2020.1728384

关键词

Molecular dynamics; Parkinson's disease; protein misfolding; protein aggregation

资金

  1. Tezpur University
  2. University Grants Commission, India

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Parkinson's disease is a common progressive neurodegenerative disorder caused by misfolding and aggregation of alpha-synuclein. Recent research shows that Oleuropein aglycone (OleA) stabilizes the monomeric structure of alpha-synuclein, preventing the formation of toxic aggregates and favoring the growth of stable ones, highlighting a potential therapeutic approach.
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 (alpha-synuclein). It is characterized by distinct aggregated fibrillary form of alpha-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 alpha-synuclein. Recently, Oleuropein aglycone (OleA) has been reported to stabilize the monomeric structure of alpha-synuclein, subsequently favoring the growth of nontoxic aggregates. Therefore, understanding the conformational dynamics of alpha-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 alpha-synuclein using molecular dynamics simulation. From molecular dynamics trajectory analysis, we noticed that when OleA is bound to alpha-synuclein, the intramolecular distance between non-amyloid-beta component domain and C-terminal domain of alpha-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 alpha-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 alpha-synuclein and OleA to be indeed high (Delta G(bind) = -12.56 kcal mol(-1) from MM-PBSA and Delta G(bind) = -27.41 kcal mol(-1)from MM-GBSA). Our findings in this study thus substantiate the effect of OleA on the structure and stabilization of alpha-synuclein monomer that subsequently favors the growth of stable and nontoxic aggregates. Communicated by Ramaswamy H. Sarma

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