Functional, structural and molecular dynamics correlates of voltage sensors: Implications for gating mechanisms

The four main voltage-sensors of sodium channels appear different with respect to their number of positive charges and to the presence and position of a proline residue. Peptides mimicking S4s extended with the short L45 intracellular loops from the four homologous domains of the electric eel sodium channel have been prepared. Macroscopic conductance experiments pointed to a moderate voltage-sensitivity for repeat IV (no Proline residue), an average number of four monomers involved in the conducting aggregates and some sodium selectivity. The three other S4L45s (Pro 19 in I and II) and especially repeat III (Pro 14) were much more voltage-sensitive but non-selective for sodium. The conformational transition (from helix to extended) shown to occur with an increase of the solvent dielectric constant was broader with repeat III. Molecular dynamics simulations on one of the Pro-containing S4L45 were carried out as a function of applied voltage. These simulations showed a differential insertion of the S4 and L45 moieties. Functional and conformational correlations are thus tuned to the presence and position of a single proline and suggest alternative gating mechanisms that would be in line with previous theoretical studies.