TY - JOUR TI - Conformational characterization of the intrinsically disordered protein α-Synuclein DO - https://doi.org/doi:10.7282/T33J3BPS PY - 2012 AB - Proteins 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. KW - Biochemistry KW - Protein folding KW - Amino acids--Metabolism--Disorders KW - Nervous system--Degeneration LA - eng ER -