Secondary structure determines electron transport in peptides.

Proteins play a key role in biological electron transport, but the structure-function relationships governing the electronic properties of peptides are not fully understood. Despite recent progress, understanding the link between peptide conformational flexibility, hierarchical structures, and electron transport pathways has been challenging. Here, we use single-molecule experiments, molecular dynamics (MD) simulations, nonequilibrium Green's function-density functional theory (NEGF-DFT), and unsupervised machine learning to understand the role of secondary structure on electron transport in peptides. Our results reveal a two-state molecular conductance behavior for peptides across several different amino acid sequences. MD simulations and Gaussian mixture modeling are used to show that this two-state molecular conductance behavior arises due to the conformational flexibility of peptide backbones, with a high-conductance state arising due to a more defined secondary structure (beta turn or 310 helices) and a low-conductance state occurring for extended peptide structures. These results highlight the importance of helical conformations on electron transport in peptides. Conformer selection for the peptide structures is rationalized using principal component analysis of intramolecular hydrogen bonding distances along peptide backbones. Molecular conformations from MD simulations are used to model charge transport in NEGF-DFT calculations, and the results are in reasonable qualitative agreement with experiments. Projected density of states calculations and molecular orbital visualizations are further used to understand the role of amino acid side chains on transport. Overall, our results show that secondary structure plays a key role in electron transport in peptides, which provides broad avenues for understanding the electronic properties of proteins.

Origin of Secondary Structure Transitions and Peptide Self-Assembly Propensity in Trifluoroethanol-Water Mixtures.

Membrane-peptide interactions are key to the formation of helical intermediates in the early stages of amyloidogenesis. Aqueous solutions of 2,2,2-trifluoroethanol (TFE) provide a membrane-mimetic environment capable of promoting and stabilizing local peptide interactions. Uperin 3.5 (U3.5), a 17-residue and amidated antimicrobial peptide, is unstructured in water but self-assembles into fibrils in the presence of salt. Secondary structure transitions linked to U3.5 self-assembly were investigated in TFE/water mixtures, in both the absence and presence of salt, to assess the role of membrane-peptide interactions on peptide self-assembly and amyloid formation. A 5-to-7-fold increase in fibril yield of U3.5 was observed at low TFE concentrations (10% TFE/water v/v) compared with physiological buffer but only in the presence of salt. No aggregation was observed in salt-free TFE/water mixtures. Circular dichroism spectra showed that partial helical structures, initially stabilized by TFE, transitioned to ß-sheet-rich aggregates in a saline buffer. Molecular dynamics simulations confirmed that TFE and salt act synergistically to enhance peptide-peptide interactions, resulting in ß-sheet-rich U3.5 oligomers at low TFE concentrations. Specifically, TFE stabilized amphipathic, helical intermediates, leading to increased peptide-peptide attraction through hydrophobic interactions. The presence of salt further enhanced the peptide-peptide interactions by screening positively charged residues. Thus, the study revealed the role of a membrane mimic in stabilizing helical intermediates on the pathway to amyloid formation in the antimicrobial U3.5 peptide.

Shape-persistent ladder molecules exhibit nanogap-independent conductance in single-molecule junctions.

Molecular electronic devices require precise control over the flow of current in single molecules. However, the electron transport properties of single molecules critically depend on dynamic molecular conformations in nanoscale junctions. Here we report a unique strategy for controlling molecular conductance using shape-persistent molecules. Chemically diverse, charged ladder molecules, synthesized via a one-pot multicomponent ladderization strategy, show a molecular conductance (d[log(G/G0)]/dx ≈ -0.1 nm-1) that is nearly independent of junction displacement, in stark contrast to the nanogap-dependent conductance (d[log(G/G0)]/dx ≈ -7 nm-1) observed for non-ladder analogues. Ladder molecules show an unusually narrow distribution of molecular conductance during dynamic junction displacement, which is attributed to the shape-persistent backbone and restricted rotation of terminal anchor groups. These principles are further extended to a butterfly-like molecule, thereby demonstrating the strategy's generality for achieving gap-independent conductance. Overall, our work provides important avenues for controlling molecular conductance using shape-persistent molecules.