Single-Molecule Conductance of Non-Redox Proteins: Mechanisms, Measurements, and Applications.

Charge transport underpins essential biological processes, including cellular respiration, photosynthesis, and enzymatic catalysis. Advances in molecular electronics have enabled single-molecule measurements that unequivocally establish redox-active proteins as efficient electron conductors, with their metal cofactors serving as intrinsic redox relays. By contrast, ubiquitous non-redox proteins lacking such redox centers have long been considered poor conductors. However, recent research has challenged this view, demonstrating that efficient charge transport in non-redox proteins can be mediated through polypeptide backbones, aromatic side-chain arrays, and hydrogen bond networks. This review surveys progress in understanding the single-molecule conductance of non-redox proteins. Firstly, we elucidate the fundamental transport mechanisms, highlighting the interplay between coherent tunneling and thermally activated hopping. We then provide an overview of state-of-the-art experimental techniques for single-molecule characterization. Through analysis of diverse systems spanning short peptides to large enzymes, we illustrate how aromatic amino acid networks and dynamic conformational fluctuations govern conductance, enabling emerging applications in label-free biosensing and single-molecule protein/DNA sequencing. Finally, we discuss persistent challenges and outline future opportunities for integrating protein-based conductors into bioelectronic devices. This review aims to stimulate further research and pave the way for novel applications harnessing protein conductance.