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

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 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 (ΔG_bind = –12.56 kcal mol⁻¹ from MM-PBSA and ΔG_bind = –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

Keywords:

• Molecular dynamics
• Parkinson’s disease
• protein misfolding
• protein aggregation

Acknowledgements

The authors acknowledge Tezpur University and University Grants Commission, India, for the start-up grant. The authors also thank Dr. Reetamoni Narzary, Assistant Professor in the Department of English and Foreign Languages, Tezpur University and Ms. Navamallika Dutta, Integrated MSc student of Department of Molecular Biology and Biotechnology, Tezpur University for going through sentence structure and language corrections in this manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Financial disclosure

The authors declare no competing financial interest.

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.