The substitution E452Q loses a H-bond interaction with W46 in the predicted open conformation of Q452^hASIC1a. (A and B) Side view of the predicted closed (A) and open (B) conformations of E452Q, highlighting altered interaction networks (compare with Fig. 5 A) formed by residues Q452, T26, W46, and H32. (C) R452 retains interactions with H32 in closed and with W46 in open states enabling small currents. A452, which does not interact with any residue, is not functional. (D) G28 does not make a stabilizing contact with the GAS belt in closed or open conformations resulting in complete loss of function.