Li, ZhaoJoshi, Soumil Y.Wang, YinDeshmukh, Sanket A.Matson, John B.2023-06-292023-06-292023-051433-7851http://hdl.handle.net/10919/115580We report three constitutionally isomeric tetrapeptides, each comprising one glutamic acid (E) residue, one histidine (H) residue, and two lysine (K-S) residues functionalized with side-chain hydrophobic S-aroylthiooxime (SATO) groups. Depending on the order of amino acids, these amphiphilic peptides self-assembled in aqueous solution into different nanostructures:nanoribbons, a mixture of nanotoroids and nanoribbons, or nanocoils. Each nanostructure catalyzed hydrolysis of a model substrate, with the nanocoils exhibiting the greatest rate enhancement and the highest enzymatic efficiency. Coarse-grained molecular dynamics simulations, analyzed with unsupervised machine learning, revealed clusters of H residues in hydrophobic pockets along the outer edge of the nanocoils, providing insight for the observed catalytic rate enhancement. Finally, all three supramolecular nanostructures catalyzed hydrolysis of the l-substrate only when a pair of enantiomeric Boc-l/d-Phe-ONp substrates were tested. This study highlights how subtle molecular-level changes can influence supramolecular nanostructures, and ultimately affect catalytic efficiency.application/pdfenCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 InternationalConstitutional IsomersEnantioselectivityPeptidesSelf-AssemblySimulationArticle - Refereedhttps://doi.org/10.1002/anie.202303755371949411521-3773