Analysis on molecular-level requirement to control the 3D morphologies of peptide foldamer self-assembly

Abstract

De novo design of protein-like 3D assemblies from exclusively unnatural peptides is a formidable task because the underlying principles governing the self-assembly process have not yet been well-established. To tackle this challenging issue, I performed systematic self-assembly studies using a series of congener hexapeptide foldamers to find a relationship between the foldamer’s primary sequence and the resulting self-assemblies. A scanning monomer for subtle electronic perturbation on hydrophobic foldamers induced a previously inaccessible solid-state conformational split sequence-specifically. This finding enabled me to identify the most susceptible site for the foldamer association, akin to critiral residues in natural proteins. By regulating the residue, I proved that a controlled mutation in the foldamer sequence could induce a predictable geometric switch and thereby generate customized assemblies. This study will be helpful in designing artificial peptides from scratch to create the peptidomimetic versions of structural and functional hierarchy comparable to proteins.