Accessibility via the fenestrations to drug compounds and lipid tails. (A) Percentage likelihood for each drug to occupy the pore or the four fenestrations. (B) Representative 2D averaged volumetric density map of lipid tail atoms (from neutral flecainide metadynamics simulations) showing the varied extent of lipids occupying the four fenestrations, where darker regions indicate a greater presence of lipid atoms throughout all simulations. (C) Representative snapshot of POPC lipid tails occupying fenestrations (in non-biased simulations) in the absence of a pore-blocker. (D) Representative snapshot of the absence of POPC tail in the DII–III fenestration when a drug is bound. (E) Average of the lipid tail density values for each of the four regions defined as the fenestrations; n = 9 measured across the nine different drugs metadynamics simulations; error bars indicate standard error of the mean (SEM). (F) Summarizing the spectrum of drug binding preference in the Na_v channel pore. (G) Simplified schematic of the two modes of drug occupation in the fenestrations as opposed to the central pore cavity.