A Temperature‐Driven, Reversible, Helical‐Handedness Inversion in Peptaibol Analogues Tuned by the C‐Terminal Capping Moiety

Abstract

Trichogin is a natural peptide endowed with antimicrobial and antitumor activity. A member of the peptaibol family, trichogin possesses a C‐terminal amino alcohol. In the past, this moiety was substituted for a methyl ester for synthetic purposes and it was observed that this apparently slight modification caused significant changes in the peptide bioactivity. With the aim of understanding the reasons behind such observations, a detailed spectroscopic study on a number of trichogin analogues has been performed. Herein, data obtained from synchrotron radiation circular dichroism, NMR spectroscopy, and fluorescence spectroscopy in organic solvents at cryogenic temperatures are compared with those independently acquired by means of EPR spectroscopy at 80 K. It is unambiguously revealed that the presence of a reversible, temperature‐driven, screw‐sense interconversion from a right‐ to left‐handed helix is determined by the C‐terminal capping moiety. Data demonstrate, for the first time, the key role of a C‐terminal methyl ester in promoting peptide screw‐sense inversion.

A Peptide-Based Trap for Metal Ions Studied by Electron Paramagnetic Resonance

“…The spectral values are close to those of a monoradical species, but with a bit of extra line broadening (the peak-to-peak width of the central transition is 0.35 mT, while for mono-labeled trichogins, values of 0.26-0.33 mT were reported [44]). Previously, for Tri 1,8 in a polar solvent, we found the TOAC 1 -TOAC 8 distance to be above 1.5 nm [24]. Therefore, the broadening cannot be attributed to a through-space exchange coupling.…”

“…In the literature, on the basis of conformational studies (by circular dichroism, 2D-NMR, X-ray diffraction analysis), it was suggested that a pivotal role in analyte binding is played by the central, flexible -Gly 5 -Gly 6 -motif of trichogin [49], which may form a loop around the metal ion, combined with the relatively short length of trichogin (ca. 2.2 nm in a 3 10 -helix [24,44]). These features may provide either a structural match for the coordination shell of the metal ion or the right coordination number for specific ions.…”

“…The double spin-labeled analog of trichogin GA IV Tri 1,8 [24] was produced in good yield by solid-phase peptide synthesis, following a published procedure [50,51]: nOct-TOAC 1 -Gly-Leu-Aib-Gly-Gly-Leu-TOAC 8 -Gly-Ile-Leu-Lol, Tri 1,8…”

“…One of the most common reactions of peptides to an external stimulus is to undergo a conformational change that might be reversible [18][19][20]. The activation can be triggered by a non-covalent interaction between the analyte and the peptide binding site or induced by temperature or pressure variation or light [21][22][23][24][25]. When a peptide is exploited in a smart biodevice, a clear knowledge of its physicochemical parameters and 3D structure in the 'switched on/off' states is therefore required.…”

“…The characterization at the molecular level is typically performed by several techniques: 2D NMR, circular dichroism, and X-ray diffraction for probing peptide helicity; FRET for identifying the analyte binding and for estimating the structural changes in the recipient; molecular dynamic and DFT calculations for predicting the binding site, to be compared with experimental data; microscopies for characterizing peptide supramolecular organizations, fluorescence spectroscopy for studying peptide-ion binding and revealing the complex structure, isothermal titration calorimetry, mass spectrometry, as well as other methods [7,19,22,24,[30][31][32][33][34][35].…”