Metal ion‐mediated assembly of peptides is an intriguing method for developing novel biomaterials. In particular, peptide building blocks based on collagen triple helical and coiled‐coil peptides have been functionalized with metal‐binding ligands and assemble into hierarchical structures with diverse potential applications. This review outlines the use of metal‐mediated assembly with these supramolecular structures and highlights how changes in the building blocks lead to significant differences in structural morphologies, with the identity of the metal‐binding ligands and their placement on the building block as crucial aspects in the bottom‐up development of the assemblies.
Metal-Promoted Higher-Order Assembly of Disulfide-Stapled Helical Barrels
Peptide-based helical barrels are a noteworthy building block for hierarchical assembly, with a hydrophobic cavity that can serve as a host for cargo. In this study, disulfide-stapled helical barrels were synthesized containing ligands for metal ions on the hydrophilic face of each amphiphilic peptide helix. The major product of the disulfide-stapling reaction was found to be composed of five amphiphilic peptides, thereby going from a 16-amino-acid peptide to a stapled 80-residue protein in one step. The structure of this pentamer, 5HB1, was optimized in silico, indicating a significant hydrophobic cavity of ~6 Å within a helical barrel. Metal-ion-promoted assembly of the helical barrel building blocks generated higher order assemblies with a three-dimensional (3D) matrix morphology. The matrix was decorated with hydrophobic dyes and His-tagged proteins both before and after assembly, taking advantage of the hydrophobic pocket within the helical barrels and coordination sites within the metal ion-peptide framework. As such, this peptide-based biomaterial has potential for a number of biotechnology applications, including supplying small molecule and protein growth factors during cell and tissue growth within the matrix.
more » « less- Award ID(s):
- 2108722
- PAR ID:
- 10545001
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- Nanomaterials
- Volume:
- 13
- Issue:
- 19
- ISSN:
- 2079-4991
- Page Range / eLocation ID:
- 2645
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Peptide self‐assembly is fast evolving into a powerful method for the development of bio‐inspired nanomaterials with great potential for many applications, but it remains challenging to control the self‐assembling processes and nanostrucutres because of the intricate interplay of various non‐covalent interactions. A group of 28‐residue α‐helical peptides is designed including NN, NK, and HH that display distinct hierarchical events. The key of the design lies in the incorporation of two asparagine (Asn) or histidine (His) residues at the
a positions of the second and fourth heptads, which allow one sequence to pack into homodimers with sticky ends through specific interhelical Asn‐Asn or metal complexation interactions, followed by their longitudinal association into ordered nanofibers. This is in contrast to classical self‐assembling helical peptide systems consisting of two complementary peptides. The collaborative roles played by the four main non‐covalent interactions, including hydrogen‐bonding, hydrophobic interactions, electrostatic interactions, and metal ion coordination, are well demonstrated during the hierarchical self‐assembling processes of these peptides. Different nanostructures, for example, long and short nanofibers, thin and thick fibers, uniform metal ion‐entrapped nanofibers, and polydisperse globular stacks, can be prepared by harnessing these interactions at different levels of hierarchy. -
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ABSTRACT The COVID‐19 pandemic drove a uniquely fervent pursuit to explore the potential of peptide, antibody, protein, and small‐molecule‐based antiviral agents against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). The interaction between the SARS‐CoV2 spike protein with the angiotensin‐converting enzyme 2 (ACE2) receptor that mediates viral cell entry was a particularly interesting target given its well‐described protein–protein interaction (PPI). This PPI is mediated by an α‐helical portion of ACE2 binding to the receptor binding domain (RBD) of the spike protein and thought to be susceptible to blockade through molecular mimicry. Small numbers of hydrocarbon‐stapled synthetic peptides designed to disrupt or block this interaction were tested individually and were found to have variable efficacy despite having related or overlapping sequences and similarly increased α‐helicity. Reasons for these differences are unclear and reported preclinical successes have been limited. This study sought to better understand reasons for these differences through evaluation of a comprehensive collection of hydrocarbon‐stapled peptides, designed based on four distinct principles: stapling position, number of staples, amino acid sequence, and primary sequence length. Surprisingly, we observed that the helicity and amino acid sequence iterations of hydrocarbon‐stapled peptides did not correlate with their bioactivity. Our results highlight the importance of iterative and combinatorial testing of these compounds to determine a configuration that best mimics natural binding and allows for chain flexibility while sacrificing structural helicity.
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The previously reported Q is a thermoresponsive coiled-coil protein capable of higher-order supramolecular assembly into fibers and hydrogels with upper critical solution temperature (UCST) behavior. Here, we introduce a new coiled-coil protein that is redesigned to disfavor lateral growth of its fibers and thus achieve a higher crosslinking density within the formed hydrogel. We also introduce a favorable hydrophobic mutation to the pore of the coiled-coil domain for increased thermostability of the protein. We note that an increase in storage modulus of the hydrogel and crosslinking density is coupled with a decrease in fiber diameter. We further fully characterize our α-helical coiled-coil (Q2) hydrogel for its structure, nano-assembly, and rheology relative to our previous single domain protein, Q, over the time of its gelation demonstrating the nature of our hydrogel self-assembly system. In this vein, we also characterize the ability of Q2 to encapsulate the small hydrophobic small molecule, curcumin, and its impact on the mechanical properties of Q2. The design parameters here not only show the importance of electrostatic potential in self-assembly but also provide a step towards predictable design of electrostatic protein interactions.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/nano13192645
