Background: Amyloid fibrils represent stable form of many misfolded proteins associated
with numerous diseases like Parkinson's Disease (PD), Type II diabetes and Alzheimer's disease
(AD). α-synuclein protein is the principal constituent of Lewy bodies that are considered to be pathological
hallmark of PD. Recently, a high resolution structure of α-synuclein protein that stacks together
forming fibrils in brains of PD patients were identified. What structural features drive pathology
of PD can now be possibly answered from the fibril structure of protein.
Objectives: To understand the molecular interactions those are responsible for the stability of the α-
synuclein fibril structure.
Methods: To study the molecular interactions stabilizing the α-synuclein fibril, we have used a high
resolution amyloid fibril structure (PDB ID 2N0A). The molecular interactions in fibril structure were
studied using PDBSum server. We then looked into the destabilization of α-synuclein fibril by disrupting
the salt-bridge holding the strands and probable methods to decompose fibril into structurally distinct
units using Top-domain web-server. The effect of salt-bridges on the stability of the fibril structure
was studied by mutating one of the residues involved in the formation of salt-bridge using molecular
Results: Our results indicate a finite salt-bridge (E46-K80) is crucial for stability of protofibril. Besides,
we observed hydrogen bonds and non-bonded contacts involved in fibril stabilization. We noticed
α-synuclein dimer predominantly exists in conformations distinct from fibril.
Conclusion: We characterized the salient molecular interactions in α-synuclein fibril and these findings
may be useful to design potential inhibitors for the treatment of PD.