Title:Conformational Dynamics of Post-Translational-Modified α-Synuclein
(pY39 and pS87) and its Interaction with Lipid Membrane
Volume: 13
Issue: 2
Author(s): Dorothy Das and Venkata Satish Kumar Mattaparthi*
Affiliation:
- Molecular Modelling and Simulation Laboratory, Department of Molecular Biology and Biotechnology, Tezpur
University, Tezpur-784 028, Assam, India
Keywords:
Membrane dynamics, phosphorylated α-Syn, protein aggregation, molecular dynamics, α-Synuclein, parkinson’s disease.
Abstract:
Background: The biological function of α-Synuclein (α-Syn), which includes controlling
synaptic vesicles, is regulated by phosphorylation at the Tyrosine 39 (pY39) residue. This
function can be important for both normal and aberrant functions, and it relies on the interaction
of α-Syn with the lipid membrane. pY39 α-Syn is found to form morphologically distinct fibrils
relative to wild-type (WT) α-Syn and shows less affinity to negatively charged vesicles. Also, the
phosphorylation at position Serine 87 (pS87) is increased in synucleinopathies, which inhibits α-
Syn oligomerization and affects the interaction between α-Syn and the membrane.
Objective: This work aimed to study the effects of post-translation modifications of α-Syn (pY39
and pS87) using all-atom Molecular Dynamics (MD) simulation.
Method: In this computational study, we used all-atom MD simulations to investigate the effects
of phosphorylation (pY39 and pS87) on protein-membrane interaction. The MD trajectories obtained
were analyzed, and secondary structural content was calculated using YASARA software
to perform a salt-bridge interaction study. Also, Principal component analysis was performed to
analyze the secondary minima and global minima of the phosphorylated proteins.
Results: From the MD study, we observed that phosphorylation at the Tyr 39 position in α-Syn
has a marked effect on its interaction with the lipid membrane. The conformational snapshots of
α-Syn obtained showed a high degree of fluctuations in the N-terminal region that disrupts the helix-
2 binding region. The secondary structures of pS87 α-Syn were found to be retained and influence
the NAC region to immerse into the membrane while inhibiting the potential to interact with
other neighbouring molecules. Moreover, it was observed that in the case of pY39 α-Syn as opposed
to pS87 α-Syn, there were larger energy disparities between the local and global minima of
the overall structure.
Conclusion: Therefore, disruption of the helix-2 binding region may affect the binding to the lipid
membrane and take over interaction with other proteins or vesicles. In the case of pS87 α-Syn, the
structure showed higher stability, but the NAC domain was found to emerge out of the membrane.