(
A) Comparison of solvent accessibility data reported by
Bell et al. (2004);
Vemana et al. (2004) (left plot) and calculated from the MD simulations (right plot). Solvent accessibility is estimated experimentally as a rate of modification by MTSET and in the simulations as the surface area accessible to MTSET (SASA). For the simulations, the data was collected from the six voltage sensors that underwent activation; each data point corresponds to the average SASA estimated for one voltage sensor. The values for the resting (Up) state are shown as filled cyan circles, and those for the activated (Down) state as open red circles. (
B) Models of the voltage sensor domains in the resting (Up) and activated (Down) conformations with residues in panel A highlighted. Residues accessible in both states are colored in cyan, and residues accessible mostly in the activated state are colored in red. (
C) A cartoon highlighting the key features of the two possible models for hyperpolarization-dependent gating. In the canonical helical screw motion, the S4 translates across the membrane in a helical screw motion, past the charge transfer center within the gating scaffold. Our MD simulations of HCN1 channel show that the S4 helix moves down and breaks into two parts with the lower helix becoming almost parallel to the membrane.