Molecular Simulations of the Fluctuating Conformational Dynamics of Intrinsically Disordered Proteins

TL;DR

This paper develops multiscale molecular simulations to study the conformational dynamics of intrinsically disordered proteins, specifically alpha-synuclein, calibrated to experimental data, revealing their intermediate disordered state and potential for aggregation.

Contribution

The study introduces calibrated all-atom, united-atom, and coarse-grained Langevin dynamics simulations for alpha-synuclein, enabling detailed analysis of IDP behavior and aggregation mechanisms.

Findings

Alpha-synuclein exhibits intermediate disordered conformations.

Simulations match recent smFRET experimental data.

Physical force-based simulations facilitate aggregation studies.

Abstract

Intrinsically disordered proteins (IDPs) do not possess well-defined three-dimensional structures in solution under physiological conditions. We develop all-atom, united-atom, and coarse-grained Langevin dynamics simulations for the IDP alpha-synuclein that include geometric, attractive hydrophobic, and screened electrostatic interactions and are calibrated to the inter-residue separations measured in recent smFRET experiments. We find that alpha-synuclein is disordered with conformational statistics that are intermediate between random walk and collapsed globule behavior. An advantage of calibrated molecular simulations over constraint methods is that physical forces act on all residues, not only on residue pairs that are monitored experimentally, and these simulations can be used to study oligomerization and aggregation of multiple alpha-synuclein proteins that may precede amyloid formation.