In Silico Stability Analysis and Phosphorylation Induced Structural Simulation of Alpha-synuclein in Parkinson’s disease

Abstract

Alpha-synuclein (α-syn) is the major component of pathologic inclusions that characterizes neurodegenerative disorders such as Parkinson’s disease (PD), dementia with Lewy body disease, and multiple system atrophy. Mutations and phosphorylation of α-syn causes familial PD. Phosphorylation of α-syn at TYR125 and SER129 plays an important role in PD and enhances its partial digestion by calpains leading to its aggregation; however, the exact mechanism is unknown. The present study uses in silico based approach to unravel this obscure mechanism. Phosphorylation of residues Ser-87, Tyr-125 and Ser-129 was performed for both wild-type and reported mutations, viz., A53T, A30P, and E46K. The authors modeled and validated these mutants and also analyzed the energy variation (force fields) to correlate their significance in stability of proteins. Noteworthy implications include changes in stability of proteins after being simulated using NAMD (VMD). The degradation of the protein by proteolytic enzyme calpain leads to the formation of β-sheet-like oligomer which further gives rise to Lewy bodies which is the hallmark of PD.

Keywords: α-synuclein, phosphorylation, amyloid, mutations, simulation, NAMD (VMD), protein-protein docking