Solvent Environment Influences Molecular Conformation and Electron Transport in Peptides

Hierarchical structures play a key role in governing the electronic properties of peptides. Despite recent advances, establishing clear structure-property relationships that connect the solvent environment, molecular conformation, and electron transport at the single-molecule level remains challenging. Here, we use a combination of single-molecule experiments, molecular dynamics (MD) simulations, and machine learning (ML) analysis to understand how electron transport in peptides depends on solvent conditions for several different environments including water, 2,2,2-trifluoroethanol, acetonitrile, and glycerol. Our results reveal two distinct conductance populations for peptides in water or 2,2,2-trifluoroethanol: a high-conductance state associated with defined secondary structures (β turns or 3₁₀ helices) and a low-conductance state corresponding to extended primary structures. Peptides show a diminished high-conductance state in acetonitrile, which is known to weakly stabilize secondary structures and denature peptides. Interestingly, the high-conductance state is diminished in glycerol for tetrapeptides but not for pentapeptides. Unsupervised ML analysis using silhouette clustering and Gaussian mixture modeling suggests that solvent-dependent conductance behavior is mediated by peptide conformation. Complementary MD simulations, time-lagged independent component analysis of intramolecular hydrogen-bonding (H-bonding) distances, and Pearson correlation coefficients further reveal how solvent-peptide interactions and secondary structures govern electron transport pathways. Overall, our results show that the solvent environment significantly influences electron transport in peptides mediated by secondary structure and H-bonding interactions.