Conformational dynamics of A30G α-synuclein that causes familial Parkinson disease.

The first gene shown to be responsible for autosomal-dominant Parkinson's disease (PD) is the SNCA gene, which encodes for alpha synuclein (α-Syn). Recently, a novel heterozygous A30G mutation of the SNCA gene associated with familial PD has been reported. However, little research has been done on how the A30G mutation affects the structure of α-Syn. So, using atomistic molecular dynamics (MD) simulation, we demonstrate here the key structural characteristics of A30G α-Syn in the free monomer form and membrane associated state. From the MD trajectory analysis, the structure of A30G α-Syn was noticed to exhibit rapid conformational change, increase in backbone flexibility near the site of mutation and decrease in α-helical propensity. The typical torsion angles in residues (Val26 and Glu28) near the mutation site were observed to deviate significantly in A30G α-Syn. In the case of membrane bound A30G α-Syn, the regions that were submerged in the lipid bilayer (N-helix (3-37) and turn region (38-44)) found to contain higher helical content than the elevated region above the lipid surface. The bending angle in the helix-N and helix-C regions were noticed to be relatively higher in the free form of A30G α-Syn (38.5 0 ) than in the membrane bound form (37 0 ). The A30G mutation in α-Syn was predicted to have an impact on the stability and function of the protein based on ΔΔ G values obtained from the online servers. Our results demonstrate that the A30G mutation in α-Syn altered the protein's α-helical structure and slightly altered the membrane binding.Communicated by Ramaswamy H. Sarma.