Gramicidin S is a naturally occurring antimicrobial cyclic peptide. Herein, we present a series of cyclic peptides based on gramicidin S that contain an azobenzene photoswitch to reversibly control secondary structure and, hence, antimicrobial activity. 1H NMR spectroscopy and density functional theory calculations revealed a β‐sheet/β‐turn secondary structure for the cis configuration of each peptide, and an ill‐defined conformation for all associated trans structures. The cis‐enriched and trans‐enriched photostationary states (PSSs) for peptides 1–3 were assayed against Staphylococcus aureus to reveal a clear relationship between well‐defined secondary structure, amphiphilicity and optimal antimicrobial activity. Most notably, peptides 2 a and 2 b exhibited a fourfold difference in antimicrobial activity in the cis‐enriched PSS over the trans‐enriched equivalent. This photopharmacological approach allows antimicrobial activity to be regulated through photochemical control of the azobenzene photoswitch, thereby opening new avenues in the design and synthesis of future antibiotics.
The
fabrication of solid-state single-molecule switches with high
on–off conductance ratios has been proposed to advance conventional
technology in areas such as molecular electronics. Herein, we employed
the scanning tunneling microscope break junction (STM-BJ) technique
to modulate conductance in single-molecule junctions using mechanically
induced stretching. Compound 1a possesses two dihydrobenzothiophene
(DHBT) anchoring groups at the opposite ends linked with rigid alkyne
side arms to form a gold–molecule–gold junction, while 1b contains 4-pyridine-anchoring groups. The incorporation
of ferrocene into the backbone of each compound allows rotational
freedom to the cyclopentadienyl (Cp) rings to give two distinct conductance
states (high and low) for each. Various control experiments and suspended
junction compression/retraction measurements indicate that these high-
and low-conductance plateaus are the results of conformational changes
within the junctions (extended and folded states) brought about by
mechanically induced stretching. A high–low switching factor
of 42 was achieved for 1a, whereas an exceptional conductance
ratio in excess of 2 orders of magnitude (205) was observed for 1b. To the best of our knowledge, this is the highest experimental
on–off conductance switching ratio for a single-molecule junction
exploiting the mechanically induced STM-BJ method. Computational studies
indicated that the two disparate conductance states observed for 1a and 1b result from mechanically induced conformational
changes due to an interplay between conductance and the dihedral angles
associated with the electrode–molecule interfaces. Our study
reveals the structure–function relationship that determines
conductance in such flexible and dynamic systems and promotes the
development of a single-molecule variable resistor with high on–off
switching factors.
The majority of the protein structures have been elucidated under equilibrium conditions. The aim herein is to provide a better understanding of the dynamic behavior inherent to proteins by fabricating a label‐free nanodevice comprising a single‐peptide junction to measure real‐time conductance, from which their structural dynamic behavior can be inferred. This device contains an azobenzene photoswitch for interconversion between a well‐defined cis, and disordered trans isomer. Real‐time conductance measurements revealed three distinct states for each isomer, with molecular dynamics simulations showing each state corresponds to a specific range of hydrogen bond lengths within the cis isomer, and specific dihedral angles in the trans isomer. These insights into the structural dynamic behavior of peptides may rationally extend to proteins. Also demonstrated is the capacity to modulate conductance which advances the design and development of bioinspired electronic nanodevices.
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