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 structural characterization especially challenging, both experimentally
and computationally. Most all-atom force fields are designed for folded
proteins and give too compact IDP conformations. α-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 α-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 α-synuclein, such as chemical shifts, secondary
structure content, and long-range contacts, are also reproduced. Furthermore,
we have simulated a glycated form of α-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.