β‐Sheet to Helical‐Sheet Evolution Induced by Topochemical Polymerization: Cross‐α‐Amyloid‐like Packing in a Pseudoprotein with Gly‐Phe‐Gly Repeats

Hema, Kuntrapakam; Sureshan, Kana M.

doi:10.1002/ange.201914975

Cited by 12 publications

(2 citation statements)

References 78 publications

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“…A thermalinduced cross-α/cross-β transition was previously reported in a synthetic self-assembling heptapeptide, suggested to occur via an intermediate turn motif 33 . In addition, a dipeptide proteinmimics, containing triazole linkages as peptide-bond surrogate, formed β-sheet rich structures in crystals, while heat-induced polymerization into a pseudoprotein revealed transition into helical sheets resembling the cross-α configuration 37 . The seemingly relatively unstructured C-terminal region of uperin 3.5 (Figure 1), might be essential for the mechanism of cross-α/cross-β transition.…”

Section: Discussionmentioning

confidence: 99%

The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid

Salinas

Tayeb-Fligelman

Sammito

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

113

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Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 comprised antiparallel and parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 demonstrated chameleon properties of a secondary structure switch, forming mostly cross-β fibrils in the absence of lipids. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.

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Section: Discussionmentioning

confidence: 99%

The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid

Salinas

Tayeb-Fligelman

Sammito

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

113

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“…Sureshan et al [ 88 , 89 , 90 , 91 ] used another method of polymerization: topochemical azide–alkyne cycloaddition (TAAC) polymerization. This reaction makes it possible to synthesize triazolic peptidomimetics with repetitive sequences, without a catalyst and without a solvent.…”

Section: Compounds With Triazole Links To Other Featuresmentioning

confidence: 99%

1,2,3-Triazoles as Biomimetics in Peptide Science

2021

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Natural peptides are an important class of chemical mediators, essential for most vital processes. What limits the potential of the use of peptides as drugs is their low bioavailability and enzymatic degradation in vivo. To overcome this limitation, the development of new molecules mimicking peptides is of great importance for the development of new biologically active molecules. Therefore, replacing the amide bond in a peptide with a heterocyclic bioisostere, such as the 1,2,3-triazole ring, can be considered an effective solution for the synthesis of biologically relevant peptidomimetics. These 1,2,3-triazoles may have an interesting biological activity, because they behave as rigid link units, which can mimic the electronic properties of amide bonds and show bioisosteric effects. Additionally, triazole can be used as a linker moiety to link peptides to other functional groups.

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Azide⋅⋅⋅Oxygen Interaction: A Crystal Engineering Tool for Conformational Locking

et al. 2021

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We have designed, synthesized, and crystallized 36 compounds, each containing an azide group and an oxygen atom separated by three bonds. Crystal structure analysis revealed that each of these molecules adopts a conformation in which the azide and oxygen groups orient syn to each other with a short O⋅⋅⋅Nβ contact. Geometry‐optimized structures [using M06‐2X/6–311G(d,p) level of theory] also showed the syn conformation in all 36 of these cases, suggesting that this is not merely a crystal packing effect. Quantum topological analysis using Bader's Atoms in Molecules (AIM) theory revealed bond paths and bond critical points (BCP) in these structures suggesting its nature and energetics to be similar to weak hydrogen bonding. The NCI‐RDG plot clearly revealed the attractive interaction consisting of electrostatic or dispersive components in all the 36 systems. NBO analysis suggested a weak orbital‐relaxation (charge‐transfer) contribution of energy for a few (sp2)O‐donor systems. Natural population analysis (NPA) and molecular electrostatic potential mapping (MESP) of these crystal structures further revealed the existence of favorable azide‐oxygen interaction. A CSD search indicated the frequent and consistent occurrence of this interaction and its role dictating the syn conformation of azide and oxygen in molecules where these groups are separated by 2–4 bonds.

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β‐Sheet to Helical‐Sheet Evolution Induced by Topochemical Polymerization: Cross‐α‐Amyloid‐like Packing in a Pseudoprotein with Gly‐Phe‐Gly Repeats

Cited by 12 publications

References 78 publications

The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid

The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid

1,2,3-Triazoles as Biomimetics in Peptide Science

Azide⋅⋅⋅Oxygen Interaction: A Crystal Engineering Tool for Conformational Locking

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