Mexiletine shows preference for binding in both the pore cavity and fenestrations . (A–E) The mixed binding modes of mexiletine in neutral (A and C) versus protonated (B and D) form—showing the free energy surfaces (FES) reproduced from metadynamics simulations (A and B); representative binding pose of each of the top five clusters (C and D); percentage of the top five clusters where interactions between the mexiletine and protein residues were identified (E). FES contours are shown every 4 kJ/mol.