Abstract
Understanding peptide self-assembly mechanisms and stability of the formed assemblies is crucial for the development of functional nanomaterials. Herein, we have adopted a rational design approach to demonstrate how a minimal structural modification to a nonassembling ultrashort ionic self-complementary tetrapeptide FEFK (Phe4) remarkably enhanced the stability of self-assembly into β-sheet nanofibers and induced hydrogelation. This was achieved by replacing flexible phenylalanine residue (F) by the rigid phenylglycine (Phg), resulting in a constrained analogue PhgEPhgK (Phg4), which positioned aromatic rings in an orientation favorable for aromatic stacking. Phg4 self-assembly into stable β-sheet ladders was facilitated by π-staking of aromatic side chains alongside hydrogen bonding between backbone amides along the nanofiber axis. The contribution of these noncovalent interactions in stabilizing self-assembly was predicted by in silico modeling using molecular dynamics simulations and semiempirical quantum mechanics calculations. In aqueous medium, Phg4 β-sheet nanofibers entangled at a critical gelation concentration ≥20 mg/mL forming a network of nanofibrous hydrogels. Phg4 also demonstrated a unique surface activity in the presence of immiscible oils and was superior to commercial emulsifiers in stabilizing oil-in-water (O/W) emulsions. This was attributed to interfacial adsorption of amphiphilic nanofibrils forming nanofibrilized microspheres. To our knowledge, Phg4 is the shortest ionic self-complementary peptide rationally designed to self-assemble into stable β-sheet nanofibers capable of gelation and emulsification. Our results suggest that ultrashort ionic-complementary constrained peptides or UICPs have significant potential for the development of cost-effective, sustainable, and multifunctional soft bionanomaterials.
Highlights
Molecular self-assembly has been exploited in nature for the engineering of complex higher macromolecular structures of the proteome
We have investigated the interfacial activity of the unpacked amphiphilic β-sheet ladder, which is in thermodynamic equilibrium with the packed form, for stabilizing oil-inwater (O/W) emulgels (EMGs) in biphasic media (Figure 1C).[16−19] EMGs stability was tested versus a number of commercial emulsifiers under a range of environmental and storage conditions
To the best of our knowledge, we have reported for the first time the shortest ionic self-complementary sequence (Phg[4] tetrapeptide) that self-assembles into stable amphiphilic βsheet nanofibers capable of gelation and emulsification
Summary
Molecular self-assembly has been exploited in nature for the engineering of complex higher macromolecular structures of the proteome. The bottom-up design of de novo self-assembling peptides has been extensively investigated in the last three decades to innovate a wide variety of stable nanostructures for biomedical applications.[1,2] Zhang and coworkers were the first to propose the self-assembling ionic selfcomplementary peptide sequence pattern, with alternation of hydrophobic (A) and hydrophilic charged (B) amino acids: (ABAB)n, where n is the number of the pattern repeats.[3,4] This design was inspired by the unusual sequence pattern EAK16 identified in a segment of the Z-DNA binding protein Zuotin, which was purified from the nuclear extract of the baker’s yeast Saccharomyces cerevisiae.[5].
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