Selectivity Mechanism of the Voltage-gated Proton Channel, HV1

Voltage-gated proton channels, H_V1, trigger bioluminescence in dinoflagellates, enable calcification in coccolithophores, and play multifarious roles in human health. Because the proton concentration is minuscule, exquisite selectivity for protons over other ions is critical to H_V1 function. The selectivity of the open H_V1 channel requires an aspartate near an arginine in the selectivity filter (SF), a narrow region that dictates proton selectivity, but the mechanism of proton selectivity is unknown. Here we use a reduced quantum model to elucidate how the Asp-Arg SF selects protons but excludes other ions. Attached to a ring scaffold, the Asp and Arg side chains formed bidentate hydrogen bonds that occlude the pore. Introducing H₃O⁺ protonated the SF, breaking the Asp-Arg linkage and opening the conduction pathway, whereas Na⁺ or Cl^- was trapped by the SF residue of opposite charge, leaving the linkage intact, thus preventing permeation. An Asp-Lys SF behaved like the Asp-Arg one and was experimentally verified to be proton-selective, as predicted. Hence, interacting acidic and basic residues form favorable AspH⁰-H₂O⁰-Arg⁺ interactions with hydronium but unfavorable Asp^--X^-/X⁺-Arg⁺ interactions with anions/cations. This proposed mechanism may apply to other proton-selective molecules engaged in bioenergetics, homeostasis, and signaling.