Drgkoppalu R. Puneeth Kumar

Crystalline materials exhibiting non‐centrosymmetry and possessing substantial surface dipole moments play a critical role in piezoelectricity. Designing biocompatible self‐assembled materials with these attributes is particularly challenging when compared to inorganic materials and ceramics. In this study, we elucidate the crystal conformations of novel cyclic peptides that exhibit self‐assembly into tubular structures characterized by unidirectional hydrogen bonding and piezoelectric properties. Unlike cyclic peptides derived from alternating L‐ and D‐amino acids, those derived from new δ‐amino acids demonstrate the formation of self‐assembled tubes with unidirectional hydrogen bonds. Further, the tightly packed tubular assemblies and higher macrodipole moments result in superior piezoelectric coefficients compared to peptides with lower macrodipole moments. Our findings underscore the potential for designing cyclic peptides with unidirectional hydrogen bonds, thereby paving the way for their application in design of biocompatible piezo‐ and ferroelectric materials.

Crystalline materials exhibiting non‐centrosymmetry and possessing substantial surface dipole moments play a critical role in piezoelectricity. Designing biocompatible self‐assembled materials with these attributes is particularly challenging when compared to inorganic materials and ceramics. In this study, we elucidate the crystal conformations of novel cyclic peptides that exhibit self‐assembly into tubular structures characterized by unidirectional hydrogen bonding and piezoelectric properties. Unlike cyclic peptides derived from alternating L‐ and D‐amino acids, those derived from new δ‐amino acids demonstrate the formation of self‐assembled tubes with unidirectional hydrogen bonds. Further, the tightly packed tubular assemblies and higher macrodipole moments result in superior piezoelectric coefficients compared to peptides with lower macrodipole moments. Our findings underscore the potential for designing cyclic peptides with unidirectional hydrogen bonds, thereby paving the way for their application in design of biocompatible piezo‐ and ferroelectric materials.

Chirality is ubiquitous in nature, and homochirality is manifested in many biomolecules. Although β‐double helices are rare in peptides and proteins, they consist of alternating L‐ and D‐amino acids. No peptide double helices with homochiral amino acids have been observed. Here, we report chiral β‐double helices constructed from γ‐peptides consisting of alternating achiral (E)‐α,β‐unsaturated 4,4‐dimethyl γ‐amino acids and chiral (E)‐α,β‐unsaturated γ‐amino acids in both single crystals and in solution. The two independent strands of the same peptide intertwine to form a β‐double helix structure, and it is stabilized by inter‐strand hydrogen bonds. The peptides with chiral (E)‐α,β‐unsaturated γ‐amino acids derived from α‐L‐amino acids adopt a (P)‐β‐double helix, whereas peptides consisting of (E)‐α,β‐unsaturated γ‐amino acids derived from α‐D‐amino acids adopt an (M)‐β‐double helix conformation. The circular dichroism (CD) signature of the (P) and (M)‐β‐double helices and the stability of these peptides at higher temperatures were examined. Furthermore, ion transport studies suggested that these peptides transport ions across membranes. Even though the structural analogy suggests that these new β‐double helices are structurally different from those of the α‐peptide β‐double helices, they retain ion transport activity. The results reported here may open new avenues in the design of functional foldamers.

Chirality is ubiquitous in nature, and homochirality is manifested in many biomolecules. Although β‐double helices are rare in peptides and proteins, they consist of alternating L‐ and D‐amino acids. No peptide double helices with homochiral amino acids have been observed. Here, we report chiral β‐double helices constructed from γ‐peptides consisting of alternating achiral (E)‐α,β‐unsaturated 4,4‐dimethyl γ‐amino acids and chiral (E)‐α,β‐unsaturated γ‐amino acids in both single crystals and in solution. The two independent strands of the same peptide intertwine to form a β‐double helix structure, and it is stabilized by inter‐strand hydrogen bonds. The peptides with chiral (E)‐α,β‐unsaturated γ‐amino acids derived from α‐L‐amino acids adopt a (P)‐β‐double helix, whereas peptides consisting of (E)‐α,β‐unsaturated γ‐amino acids derived from α‐D‐amino acids adopt an (M)‐β‐double helix conformation. The circular dichroism (CD) signature of the (P) and (M)‐β‐double helices and the stability of these peptides at higher temperatures were examined. Furthermore, ion transport studies suggested that these peptides transport ions across membranes. Even though the structural analogy suggests that these new β‐double helices are structurally different from those of the α‐peptide β‐double helices, they retain ion transport activity. The results reported here may open new avenues in the design of functional foldamers.

The recent approval of antibody-based therapy for targeting the clearance of amyloid plaques fuels the research in designing small molecules and peptide inhibitors to target the aggregation of Aβ-peptides. Here, we report that the 15-residue ααγ-hybrid peptide not only inhibits the aggregation of soluble Aβ₄₂ into fibrils but also disintegrates the aggregated Aβ₄₂ fibrils into smaller assemblies. Further, the hybrid peptide completely rescues neuronal cells from the toxicity of Aβ₄₂ at equimolar concentrations. The shorter 10- and 12-mer peptides showed weak aggregation inhibition activity, while the fully hydrophobic 15-mer ααγ-hybrid peptide analogue showed no aggregation inhibition activity. Further, the 15-mer ααγ-hybrid peptide showed resistance against trypsin digestion and also nontoxic to the neuronal cells. The CD revealed that the peptide upon interaction induces a helix-type conformation in the Aβ₄₂. This is in sharp contrast to the β-sheet conformation of Aβ₄₂ upon incubation. The two-dimensional-NMR (2D-NMR) analysis revealed a large perturbation in the chemical shifts of residues at the N-terminus. The presence of 15-mer peptide at an equimolar concentration of Aβ₄₂ showed less tendency for aggregation and also exhibited nontoxicity to the neuronal cells. The results reported here may be useful in designing new therapeutics for Alzheimer's disease.