(A–D) Data and structural images based on unbiased MD simulations starting from a closed structural model of hASIC1a, in which the protonation of residues mimicked pH5. (A–C) Time series reporting the average (n = three subunits) of the distance between the side chains of Ser83 and 'Gln358 (A), Ser83 and 'Glu359 (B), and Lys211 and 'Glu359. (D) Snapshots taken at the start (t = 6 ns, left) and toward the end (t = 640 ns, right) of the simulation, highlighting the switch in side chain orientation of 'Gln358 and 'Glu359, with 'Glu359 facing the solvent at start and approaching Lys211 after a few hundreds of ns, while 'Gln358 is exposed to the solvent toward the end of the simulation. Note that the switch in side chain orientation occurred in all three subunits, while the formation of the stable salt bridge occurred in one subunit interface only. The arrows indicate the distance between the center of mass of the side chain heavy atoms (Glu: OE1 and OE2, Gln: OE1, NE2, Ser: OG). (E) The hASIC1a, but not the cASIC1a structure, favors the approaching between Gln84 and Tyr417 during the open-to-desensitized transition. The homologous residues in cASIC1a are Arg85 and Tyr416. Left, structural image of hASIC1a. The frame indicates the magnified area shown in the center panel. Center, molecular representation from an MD trajectory of hASIC1a showing that Tyr417 forms a cation-π interaction with Arg279. Right, in the corresponding area of the cASIC structure (PDB 4NTW), Tyr416 also forms a cation-π interaction with Arg280 (homologous to hASIC1a-Arg279). However, in this case, Arg85 is not likely to approach this positively charged area. Note that the side chain of Arg85, except Cβ, is absent from this open as well as from the desensitized structures (PDB code 4NYK). Electrostatic interactions are symbolized with black dashed lines. Source data are provided in the file Figure 7—source data 1.