Movie S2.

Molecular dynamics simulation of hNav1.5 channel interaction with lidocaine reveals hydrophobic and hydrophilic drug access pathways. Transmembrane view ofhNav1.5 channel model (colored in light gray) with sidechains of F1760 and Y1767 shown in stick representation. Lidocaine molecule that accessed the pore lumen through the fenestration between domains III and IV is shown in spacefilling representation and colored in cyan with nitrogen atoms colored in blue and oxygen atom colored in red. Lidocaine molecule that accessed the pore lumen through the intracellular gate is shown in spacefilling representation and colored in purple. Side chains of residues that form hydrophobic access pathway for lidocaine are shown in stick representation and colored in dark gray. The pore-forming domains III and IV are shown in the front view during most of the movie. The pore-forming domains I and IV are shown in the front view at the end of the movie.