A Coarse-Grained Molecular Dynamics Approach to the Study of the Intrinsically Disordered Protein α-Synuclein

Intrinsically disordered proteins (IDPs) are not well described by a single 3D conformation but by an ensemble of them, which makes their computationally. Most all-atom force fields are designed for folded proteins structural characterization especially challenging, both experimentally and and give too compact IDP conformations. alpha-Synuclein is a well-known IDP because of its relation to Parkinson's disease (PD). To understand its role in this disease at the molecular level, an efficient methodology is needed for the generation of conformational ensembles that are consistent with its known properties (in particular, with its dimensions) and that is readily extensible to post-translationally modified forms of the protein, commonly found in PD patients. Herein, we have contributed to this goal by performing explicit-solvent, microsecond-long Replica Exchange with Solute Scaling (REST2) simulations of alpha-synuclein with the coarse-grained force field SIRAH, finding that a 30% increase in the default strength of protein water interactions yields a much better reproduction of its radius of gyration. Other known properties of alpha-synuclein, such as chemical shifts, secondary structure content, and long-range contacts, are also reproduced. Furthermore, we have simulated a glycated form of alpha-synuclein to suggest the extensibility of the method to its post-translationally modified forms. The computationally efficient REST2 methodology in combination with coarse grained representations will facilitate the simulations of this relevant IDP and its modified forms, enabling a better understanding of their roles in disease and potentially leading to efficient therapies.