Figure 7.

Accessibility of Nav1.5 fenestrations. The 2D FES of lidocaine’s occupancy within the pore cavity and fenestrations of Nav1.5, reconstructed from the hills potentials deposited during metadynamics simulations. (A) The top-down polar view (obtained by integrating out z, keeping r and θ) with the MFEP through each fenestration, colored blue, red, cyan, and magenta, ending at the minimum free energy binding site at the mouth of DI-II (note that the last section of the cyan and red pathways overlap with the magenta line). (B) Transverse views of each fenestration extending radially from the central pore axis (obtained by integrating out θ, keeping z and r, for each corresponding fenestration segment, spanning 50°, as depicted in A); MFEPs also mapped along relevant sections of the transverse fenestration axes. (C) Free energy value along the MFEPs, colored according to each fenestration, also showing the most favorable pathway along fenestration DI-II.