Azobenzene-Based Amino Acids for the Photocontrol of Coiled-Coil Peptides

Abstract

Coiled-coil peptides are high-affinity, selective, self-assembling binding motifs, making them attractive components for the preparation of functional biomaterials. Photocontrol of coiled-coil self-assembly allows for the precise localization of their activity. To rationally explore photoactivity in a model coiled coil, three azobenzene-containing amino acids were prepared and substituted into the hydrophobic core of the E3/K3 coiled-coil heterodimer. Two of the non-natural amino acids, APhe1 and APhe2, are based on phenylalanine and differ in the presence of a carboxylic acid group. These have previously been demonstrated to modulate protein activity. When incorporated into peptide K3, coiled-coil binding strength was affected upon isomerization, with the two variants differing in their most folded state. The third azobenzene-containing amino acid, APgly, is based on phenylglycine and was prepared to investigate the effect of amino acid size on photoisomerization. When APgly is incorporated into the coiled coil, a 4.7-fold decrease in folding constant is observed upon trans-to-cis isomerizationthe largest difference for all three amino acids. Omitting the methylene group between azobenzene and α-carbon was theorized to both position the diazene of APgly closer to the hydrophobic amino acids and reduce the possible rotations of the amino acid, with molecular dynamics simulations supporting these hypotheses. These results demonstrate the ability of photoswitchable amino acids to control coiled-coil assembly through disruption of the hydrophobic interface, a strategy that should be widely applicable.

Lipid-Based Nanoparticle Functionalization with Coiled-Coil Peptides for In Vitro and In Vivo Drug Delivery

“…Besides the described well-known CPPs, fusogenic coiled-coil peptides can be used to bind selectively with high affinity to a partner peptide, allowing them to overcome the plasma membrane of cells. This bypasses the endosomal pathway, making them attractive components for the preparation of vehicles for precise delivery with high transport efficiency …”

“…This bypasses the endosomal pathway, making them attractive components for the preparation of vehicles for precise delivery with high transport efficiency. 23 …”

“…17 (23), 23466−23477. 4 Building upon previous reports, we expanded our scope to lipid nanoparticles (LNPs) as delivery vehicles.…”

Modulating Secondary Structure Motifs Through Photo‐Labile Peptide Staples

“…[25,26] Moreover, the usage of photons as reagents is beneficial as they can be applied externally and are traceless reagents by nature. [27] In this manner, photoresponsive small bioactive molecules, [26,[28][29][30][31][32] nucleotides, [33][34][35][36][37] UAAs, [38][39][40][41] and peptides [41][42][43][44][45][46][47] have been developed.…”