Nano-Antimicrobial Peptides Based on Constitutional Isomerism-Dictated Self-Assembly

Abstract

Self-assembly has been identified as an innovative strategy for improving the antimicrobial efficacy and bioavailability of short peptides. However, the detailed molecular information of short peptides linking to the self-assembly structures and antimicrobial activity remains to be more clearly understood. This work reported that the constitutional isomeric sequences of cationic peptides showed a significant impact on their antimicrobial activity. We investigated the self-assembly structures of two constitutional isomeric peptides Ac-RFSFSFR-NH2 and Ac-SFRFRFS-NH2, which contained the same serine, alkaline, and phenylalanine residues but in a different order. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) revealed that the constitutional isomers self-assembled into different morphologies in an aqueous solution. The sequence with alkaline residues located at both termini of the peptide favored the formation of β-sheet conformation and nanofibers, while irregular nanospheres were observed when positioning the alkaline residues at the center of the isomeric peptide. The ζ-potential measurements showed that the Ac-RFSFSFR-NH2 nanofibers had a net potential of +17.4 mV, whereas the apparent potential of Ac-SFRFRFS-NH2 nanospheres dropped steeply to +1.0 mV. These differences of the constitutional isomeric peptides were directly reflected in their antimicrobial activities. In comparison with the peptide Ac-SFRFRFS-NH2, the constitutional isomer Ac-RFSFSFR-NH2 exhibited much higher antimicrobial efficacy against Gram-positive Staphylococcus aureus and Bacillus subtilis and Gram-negative Escherichia coli and Pseudomonas aeruginosa. Moreover, several pairs of constitutional isomeric peptides with a similar sequence layout yielded the same outcome. These collective results not only highlight the importance of the isomeric sequence on the antimicrobial efficacy of short peptides but also increase further potential in optimizing the design of self-assembled nano-antimicrobial peptides (AMPs).

Computational design of self-assembling peptide chassis materials for synthetic cells

“…We also propose that our active learning screening approach can be generically extended to other applications in biopolymer and biomolecular design where it is necessary to navigate large sequence spaces by coupling the GPR/BO approach to alternative computational and/or experimental measures of performance such as protein-ligand binding free energy 88 or antimicrobial activity. 89,90 Author contributions Table 1 Top 10 candidates identified by active learning computational screen along with their computed ΔG value, round of discovery in the active learning screen, and hydropathy score of the X 1 and X 2 guest residues under the Kyte-Doolittle hydropathy scale. 23 The abbreviation (X 1 ) m (X 2 ) n stands for (…”

“…We also propose that our active learning screening approach can be generically extended to other applications in biopolymer and biomolecular design where it is necessary to navigate large sequence spaces by coupling the GPR/BO approach to alternative computational and/or experimental measures of performance such as protein–ligand binding free energy 88 or antimicrobial activity. 89,90…”

Self-assembled peptide-based nanoblocks for drug delivery

“…S4 (ESI †), Pep1 by itself showed two bands at 1632 and 1675 cm À1 ; the band at 1632 cm À1 was assigned to the dominant random coil together with other conformations during the freeze-drying step. 39 The turn and b-sheet conformation are most likely to exist, but have very low populations. 40 The band at 1675 cm À1 was ascribed to the formation of trifluoroacetate salts during the synthesis purification process of Pep1.…”

Sequence-Isomerism-Controlled Macromolecular Self-Assembly in Dendritic Rod-Like Molecules

“…In addition, the distinct selfassembly structures of a pair of oligopeptide sequence isomers dictated the antimicrobial activity. 16 Dendrimers, or dendritic molecules with a regular branching architecture, are one of the common self-assembling macromolecules. Pioneered by Percec and co-workers, the systematic study of a series of so-called Percec-type dendrons revealed diverse-ordered nanostructures, mainly correlated to a parameter known as the molecular solid angle.…”

“…However, given the recent progress, such as the iterative exponential growth strategy, the extreme difficulties and low efficiency in synthesizing uniform, sequence-controlled macromolecules still limit the study in this direction, with a handful of examples focusing on linear macromolecules. , Changes in monomer sequence of linear block copolymers may alter the overall molecular shape, thus inducing the phase evolution from lamellae to cylinders and spheres. In addition, the distinct self-assembly structures of a pair of oligopeptide sequence isomers dictated the antimicrobial activity …”