Josephin Domain Structural Conformations Explored by Metadynamics in Essential Coordinates

The Josephin Domain (JD), i.e. the N-terminal domain of Ataxin 3 (At3) protein, is an interesting example of competition between physiological function and aggregation risk. In fact, the fibrillogenesis of Ataxin 3, responsible for the spinocerebbellar ataxia 3, is strictly related to the JD thermodynamic stability. Whereas recent NMR studies have demonstrated that different JD conformations exist, the likelihood of JD achievable conformational states in solution is still an open issue. Marked differences in the available NMR models are located in the hairpin region, supporting the idea that JD has a flexible hairpin in dynamic equilibrium between open and closed states. In this work we have carried out an investigation on the JD conformational arrangement by means of both classical molecular dynamics (MD) and Metadynamics employing essential coordinates as collective variables. We provide a representation of the free energy landscape characterizing the transition pathway from a JD op...

• Type: Journal
• Year: 2016
• Where: PLOSCB
• Authors: Marco A. Deriu, Gianvito Grasso, Jack A. Tuszynski, Diego Gallo, Umberto Morbiducci, Andrea Danani
• Keywords: PLOSCB 2016