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

Abstract

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 (38.5⁰) than in the membrane bound form (37⁰). The A30G mutation in α-Syn was predicted to have an impact on the stability and function of the protein based on ΔΔG 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

Keywords:

• A30G mutation
• α-synuclein
• molecular dynamics
• Parkinson’s disease
• membrane dynamics

Author contributions

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

Disclosure statement

The authors declare no competing financial interest.

Additional information

Funding

The authors acknowledge Science and Engineering Research Board (SERB) for the financial grant. This study was supported by the project (EMR/2017/005383) under DST-SERB. DD thanks SERB for GATE JRF fellowship.