Abstract
Intrinsically disordered proteins (IDPs) have been shown to be involved in a number of cellular functions, in addition to their predominance in diseased states. α-synuclein may be described as one such IDP implicated in the pathology of Parkinson's disease. Understanding the conformational characteristics of the monomeric state of α-synuclein is necessary for understanding the role of the monomer conformation in aggregation. Polymer theories have been applied to investigate the statistical properties of homopolymeric IDPs. Here we use Replica Exchange Molecular Dynamics (REMD) simulations using temperature as a proxy for solvent quality to examine how well these theories developed for homopolymeric chains describe heteropolymeric α-synuclein. Our results indicate that α-synuclein behaves like a homopolymer at the extremes of solvent quality, while in the intermediate solvent regime, the uneven distribution of charged residues along the sequence strongly influences the conformations adopted by the chain. We refine the ensemble extracted from the REMD simulations of α-synuclein, which shows the best qualitative agreement with experiment, by fitting to the experimental NMR Residual Dipolar Couplings (RDCs) and Paramagnetic Relaxation Enhancements (PREs). Our results demonstrate that the detailed shape of the RDC patterns are sensitive to the angular correlations that are local in sequence while longer range anti-correlations which arise from packing constraints affect the RDC magnitudes.