Identifying the Coiled-Coil Triple Helix Structure of β-Peptide Nanofibers at Atomic Resolution

Abstract

Peptide self-assembly represents a powerful bottom-up approach to the fabrication of nanomaterials. β-Peptides are non-natural peptides composed entirely of β-amino acids, which have an extra methylene in the backbone, and we reported fibers derived from the self-assembly of β-peptides that adopt 14-helical structures. β-Peptide assemblies represent a class of stable nanomaterials that can be used to generate bio- and magneto-responsive materials with proteolytic stability. However, the three-dimensional structure of many of these materials remains unknown. To develop structure-based criteria for the design of β-peptide-based biomaterials with tailored function, we investigated the structure of a tri-β-peptide nanoassembly by molecular dynamics simulations and X-ray fiber diffraction analysis. Diffraction data was collected from aligned fibrils formed by Ac-β[LIA] in water and used to inform and validate the model structure. Models with 3-fold radial symmetry resulted in stable fibers with a triple-helical coiled-coil motif and measurable helical pitch and periodicity. The fiber models revealed a hydrophobic core and twist along the fiber axis arising from a maximization of contacts between hydrophobic groups of adjacent tripeptides on the solvent-exposed fiber surface. These atomic structures of macroscale fibers derived from β-peptide-based materials provide valuable insight into the effects of the geometric placement of the side chains and the influence of solvent on the core fiber structure which is perpetuated in the superstructure morphology.

Transition of Nano-Architectures Through Self-Assembly of Lipidated β3-Tripeptide Foldamers

“…As a consequence, for the peptides used in this study, it can be proposed that the lipid side chains are all positioned on the same face of the 14-helix which provides the potential for the lipid chains are likely to align and pack in a layered arrangement. the orientation of the lipid chain on the surface of a fibril influences the lateral interactions This alignment then allows for fine control of the supramolecular structures formed by either limiting or promoting the amount of noncovalent interactions that drive lateral self-assembly and results in greater uniformity in fiber morphologies than previously described β 3 -peptides (Del Borgo et al, 2013Borgo et al, , 2018Seoudi et al, 2015Seoudi et al, , 2016Luder et al, 2016;Christofferson et al, 2018). The current results for the lipidated N-acetyl β 3 -tri-peptide foldamers therefore demonstrate a powerful design strategy to control fiber morphology through variation in the position of the alkyl chain.…”

“…Even more significantly in the context of material nanofabrication, we have shown that when N-acetylated, β 3 -peptides spontaneously self-assemble to form fibrous architectures with a large range of irregular architectures and sizes (Del Borgo et al, 2013). For example, a β 3 -tripeptide with the sequence β 3 Leu-β 3 Ile-β 3 Ala (LIA), was recently reported to self-assemble into a 14-helical coiled coil to form diverse morphologies in different solvents (Christofferson et al, 2018). Similarly, N-acetyl β 3 -peptides with the same β 3 -amino acid composition but different sequences also formed fibrous structures demonstrating sequence independent self-assembly that is unique to this class of peptides (Seoudi et al, 2015).…”

“…Therefore, in the context of material nanofabrication, given that the control of selfassembly to yield defined fiber architectures is central to future applications, there is a need to develop new strategies for finer control of these materials. The unique 14-helical selfassembly that results in lateral alignment of side chains with a high degree of symmetry along the periphery of the β 3 -peptide nanofibrils (Christofferson et al, 2018) (Figure 1) now provides the opportunity to functionalize the peptide laterally without perturbing the axial self-assembly.…”

Self‐Assembly of a β‐Peptide Foldamer: The Role of the Surfactant in Three‐Dimensional Shape Selection

“…A recent study by Yarovsky et al. showed a successful example of structural modelling of self‐assembled nanofibers of β 3 ‐peptide supported by microscopy and diffraction experiments . Herein, we focused on predicting the foldecture/water interface during self‐assembly using three slab models consisting of (001)/ , / , and (100)/ faces of the crystal structure (Figure c).…”

“…[26,27] A recent study by Yarovsky et al showed a successful example of structural modelling of selfassembled nanofibers of β 3 -peptide supported by microscopy and diffraction experiments. [28] Herein, we focused on predicting the foldecture/water interface during self-assembly using three slab models consisting of (001)/ð00 � 1Þ, ð0 � 1 � 1Þ/ð01 � 1Þ, and (100)/ ð � 100Þ faces of the crystal structure (Figure 3c). The bare surface energy (E surf ) and interaction energy between the solvent containing CTAB (0.2 g L À 1 ) and foldecture surface (Δ sol ) were calculated using following equations [Eq.…”