Voltage-gated sodium channels (NaVs) control neuronal excitability, also in association with a number of auxiliary proteins.
A comprehensive understanding of the protein-protein contact interface is instrumental in elucidating the mechanisms governing the functionality of NaV proteins and their susceptibility to genetic defects.
Over the years, our laboratory identified and characterized a proline-rich synaptic protein (PRRT2) that binds within the membrane to neuronal sodium channels, modulating their biophysical properties.
PRRT2 has been determined as the causative gene of a spectrum of neurological paroxysmal disorders, and its mutations account for many reported clinical cases. Despite experimental evidence of PRRT2-NaVs interaction, the specific contact surface remains unknown, hampering targeted molecular studies.
The study has recently made extensive use of Molecular Dynamics (MD) simulations to assess structures of both PRRT2 and sodium channels. Here, we propose to employ enhanced sampling MD simulations to compute the binding Free Energy of several putative PRRT2-NaV complexes, in order to identify the most probable interacting surfaces.
The outcomes will provide structure-based informed hypothesis for mutation experiments that will advance the knowledge on NaV channels and their modulators.
Polytechnic University of Marche - Italy