Dynamic Regulation of Proton and Water Transport through an Acylhydrazone-Based Photoresponsive Channel

Proton transport is crucial for cellular energy, and synthetic systems having the ability to control this process offer promising applications in drug development and cancer treatment. Herein we report a unique light-responsive proton/water transport system using self-assembled acylhydrazone-imidazole channels with tunable activity via <i>E</i>-<i>Z</i> isomerization. Three channel-forming molecules with varying alkyl chains were synthesized, namely, <b>1a</b> (C4), <b>1b</b> (C8), and <b>1c</b> (C12). The photoswitching behavior of the molecule was confirmed by UV-vis spectroscopy within the liposome. The crystallographic analysis revealed that the <i>E</i>-isomer forms an H-bonded proton transport pathway mediated by water molecules. Patch clamp assays confirmed proton channel formation for <b>1a</b> with a transport rate of 2.18 × 10⁷ H⁺/s/channel and high proton selectivity over other ions. Ion transport assays with EYPC-LUVs entrapped with HPTS and NaCl revealed the complete rejection of external cations and anions. The compounds demonstrated significant proton transport when combined with valinomycin, indicating transmembrane proton transport for <b>1a</b>-<b>c</b>. Upon irradiation at 310 nm, all derivatives showed increased proton transport rates, which subsequently decreased after exposure to 365 nm, confirming the photoresponsive behavior of the system. A similar trend was observed in water transport, where the single-channel permeability of <b>1a</b> increased from 6.5 × 10⁶ to 3.5 × 10⁷ water molecules/s/channel upon switching from the <i>E</i> to <i>Z</i> isomers, then decreased to 1.8 × 10⁷ after reverting to the <i>E</i> conformer. Molecular simulation confirmed that stable supramolecular porous water crystal patches may form, featuring multivalent water H-bonding to acylhydrazone and imidazole units that serve as water-cluster relays within the channel.