Nanoscale Assembly of Functional Peptides with Divergent Programming Elements

Abstract

Self-assembling peptides are being applied both in the biomedical area and as building blocks in nanotechnology. Their applications are closely linked to their modes of self-assembly, which determine the functional nanostructures that they form. This work brings together two structural elements that direct nanoscale self-association in divergent directions: proline as a β-breaker and the β-structure-associated diphenylalanine motif, into a single tripeptide sequence. Amino acid chirality was found to resolve the tension inherent to these conflicting self-assembly instructions. Stereoconfiguration determined the ability of each of the eight possible Pro-Phe-Phe stereoisomers to self-associate into diverse nanostructures, including nanoparticles, nanotapes, or fibrils, which yielded hydrogels with gel-to-sol transition at a physiologically relevant temperature. Three single-crystal structures and all-atom molecular dynamics simulations elucidated the ability of each peptide to establish key interactions to form long-range assemblies ( i,e. , stacks leading to gelling fibrils), medium-range assemblies ( i.e. , stacks yielding nanotapes), or short-range assemblies ( i.e. , dimers or trimers that further associated into nanoparticles). Importantly, diphenylalanine is known to serve as a binding site for pathological amyloids, potentially allowing these heterochiral systems to influence the fibrillization of other biologically relevant peptides. To probe this hypothesis, all eight Pro-Phe-Phe stereoisomers were tested in vitro on the Alzheimer’s disease-associated Aβ(1–42) peptide. Indeed, one nonfibril-forming stereoisomer effectively inhibited Aβ fibrillization through multivalent binding between diphenylalanine motifs. This work thus defined heterochirality as a useful feature to strategically develop future therapeutics to interfere with pathological processes, with the additional value of resistance to protease-mediated degradation and biocompatibility.

Higher-order interfiber interactions in the self-assembly of benzene-1,3,5-tricarboxamide-based peptides in water

“…In the case of F D FF, the hydrophobicity appears similar to FFF; however, three phenyl rings in F D FF cannot achieve co-planarity due to steric complications as a result of a chiral mismatch. 38 Screening of Coulomb repulsions does not affect sterical barrier resulting in almost no effect of salt addition on CAC value of F D FF.…”

From Folding to Assembly: Functional Supramolecular Architectures of Peptides Comprised of Non‐Canonical Amino Acids

“…Single‐crystal and molecular dynamics simulations revealed that the different intermolecular interactions of each isomer were responsible for long‐range, medium‐range, or short‐range assemblies. [ 33 ]…”

Nanostructured Ceria: Biomolecular Templates and (Bio)applications

“…Amyloid-associated disorders constitute a large and diverse class of pathological states of growing societal concern, as the increasing life expectancy is leading to an increasing aged population, and consequent occurrence of amyloidoses. Amongst the many potential treatments, NPs have attracted growing interest as inhibitors of amyloid aggregation, including those formed by peptides [206], carbon nanostructures [207], gold [208], and also ceria. In particular, ceria NPs were shown to bind to the α-synuclein monomer and extend the lag phase time of amyloid fibril formation, and the resulting aggregates are relatively less toxic than those formed in the absence of ceria [209].…”