Narayanan, Chitra. Conformational characterization of the intrinsically disordered protein α-Synuclein. Retrieved from https://doi.org/doi:10.7282/T33J3BPS
DescriptionProteins in their functional forms play a vital role in all major processes in the cell.
Protein misfolding has been associated with a large number of diseased states.
Intrinsically Disordered Proteins (IDPs) have gained much attention because of their
involvement in key cellular processes and predominance in diseased states. A number of
neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s
diseases have been correlated with the aggregation of IDPs.
α-synuclein is a 140 amino acid archetypal IDP implicated in the pathology of
Parkinson's disease. Aggregation of α-synuclein is sensitive to changes in amino acid
substitutions along the sequence and changes in chemical environments. Characterizing
the monomeric form is essential to understanding the conformational changes leading to
the aggregated state. In this work, ensembles of structures generated from Replica
Exchange Molecular Dynamics simulations were used to characterize aggregation-prone
states of monomeric form of α-synuclein.
The conformational characteristics of α-synuclein were evaluated in terms of the
statistical properties of the chain over a range of solvent conditions and comparing with
predictions from polymer theory, using temperature as a proxy for solvent quality.
Results of this work indicate that α-synuclein behaves as expected for a homopolymer
chain at extremes of solvent quality while at intermediate values, the identity of the
monomeric units along the sequence significantly influence the polymeric and
conformational characteristics of the chain. Comparison of the back-calculated
experimental parameters for the simulation ensemble with that of the NMR observation
shows that ensembles that fit to experimental parameters describing both local and longrange
characteristics, represented by the experimental Residual Dipolar Couplings (RDC)
and Paramagnetic Relaxation Enhancements respectively, provides a better representation
of the experimental ensemble.
The conformations of the neutral and low pH ensembles of α-synuclein were
characterized by integrating molecular simulations with experimental NMR observations,
to elucidate the effect of the altered charge distribution with change in pH on the
structural properties of these ensembles. The results from this study indicate a significant
structural reorganization with change in pH in terms of the long-range interactions,
compaction of the C-terminal region at low pH leading to faster aggregation at low pH.