Sequence and Phosphorylation Modifications Dictate Charge Transport in Cell-Penetrating Peptides for Bioelectronic Applications

Cell-penetrating peptides (CPPs) are promising building blocks for molecular bioelectronics however, how sequence and phosphorylation govern their electronic properties is unclear. Here we measured electron tunneling through self-assembled monolayers (SAMs) of short CPPs on gold using Ga₂O₃/EGaIn soft junctions. Alongside native CPPs, we studied tryptophan-enriched sequences and variants bearing site-specific phosphate groups to map how defined chemical variations affect conductance. J–V data show transport is highly sequence-sensitive: aromatic substitution and phosphorylation introduce localized dipoles that tune the tunneling barrier, shift frontier-orbital alignment, and change the net dipole moment. Phosphate position produced striking, site-dependent effects, shifting conductance by orders of magnitude across the series. Cys-Trp-(Arg)8 yielded the highest currents, whereas an Ala–Gly control was lowest—nearly an order below native R9. Relocating the phosphate along the backbone systematically modulated currents, with certain sites markedly enhancing transport. These results define a direct link between sequence chemistry and electron transport, enabling CPP-based biomolecular junctions with tunable electrical characteristics for next-generation bioelectronics.