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

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

Publication date: Feb 11, 2020

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 (?-synuclein). It is characterized by distinct aggregated fibrillary form of ?-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 ?-synuclein. Recently, Oleuropein aglycone (OleA) has been reported to stabilize the monomeric structure of ?-synuclein, subsequently favoring the growth of non-toxic aggregates. Therefore, understanding the conformational dynamics of ?-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 ?-synuclein using molecular dynamics simulation. From MD trajectory analysis, we noticed that when OleA is bound to ?-synuclein, the intramolecular distance between non-amyloid-? component (NAC) domain and C-terminal domain of ?-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 ?-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 ?-synuclein and OleA to be indeed high (?G = -12.56?kcal mol from MM-PBSA and ?G = -27.41?kcal molfrom MM-GBSA). Our findings in this study thus substantiate the effect of OleA on the structure and stabilization of ?-synuclein monomer that subsequently favors growth of stable and non-toxic aggregates.

Concepts Keywords
Aglycone Energy
Alzheimer Branches of biology
Amyloid Proteins
Binding Affinity Lewy body dementia
Brain Peripheral membrane proteins
C Terminal Neuropathology
Dyn Alpha-synuclein
Free Energy Neurological disorders
Hydrophobic Interactions Neurodegeneration
Interact Parkin
Intramolecular Amyloid
Lewy Bodies Alpha
Lipids Simulation
Misfolding
Mol
Molecular Dynamics
Monomer
N Terminal
Neurites
Neurodegenerative
OleA
Parkinson
Progressive
Simulation

Semantics

Type Source Name
disease MESH brain disorder
disease MESH growth
drug DRUGBANK Acetylcysteine

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