The Effect of Backbone-Heteroatom Substitution on the Folding of Peptides - A Single Fluorine Substituent Prevents a?-Heptapeptide from Folding into a314-Helix (NMR Analysis)

Abstract

acid residues (bhAla(X n )) of like and unlike configuration were subjected to a detailed NMR analysis in MeOH solution. For the geminal difluoro and for the F-and OH-substituted derivatives of u-configuration (see 5, 4, and 7, resp.), 14-helices were found, i.e., with axial disposition of the hetero atoms on the helix. The two compounds containing the central l-configured b-amino acid moieties (see 3 and 6) are not helical over the full lengths of the chains; they have quasi-helical termini and a central turn consisting of a ten-membered H-bonded ring (Fig. 2, d and e). Quantum-mechanical calculations with l-and u-AcNH-CHMe-CHF-CONH 2 confirm the observed preference for a conformation with antiperiplanar arrangement of the FÀC and the CO bond. The calculated energy difference between the observed non-helical geometry of this moiety and a hypothetical helical one is 6.4 kcal/mol (Fig. 3).

Fluorine as a Regiocontrol Element in the Ring Opening of Bicyclic Aziridiniums

“…The exploitation of these effects in organic and biological chemistry is currently an emerging area [38–41]. Our experimental and theoretical work illustrates how these effects result in enhanced regiocontrol in the ring-opening chemistry of bicyclic aziridiniums, complementing much of the research to date on the stereoelectronic effects of fluorine, which mostly focuses on their stereochemical ramifications [42]. …”

Helices and other secondary structures of β‐ and γ‐peptides

“…158 in a right-handed direction (a ''3.2-helix''). For steric reasons only H, OH, or F are allowed 8 in the axial positions (Figure 3), a methyl group is not. Thus, homologs of Aib (b 2 -and b 3 hAib, homoaminoisobutyric acid) are helix-breaking in the ''b-regime,'' 4 while Aib itself is strongly 3 10 -helix-inducing in the ''a-world.''…”

Exploring the Antibacterial and Hemolytic Activity of Shorter‐ and Longer‐Chain β‐, α,β‐, and γ‐Peptides, and of β‐Peptides from β2‐3‐Aza‐ and β3‐2‐Methylidene‐amino Acids Bearing Proteinogenic Side Chains – A Survey

“…One interesting observation among this set of peptides is the difference in hemolytic activity between the epimeric 2-hydroxy peptides 14 and 15 [25]. The configuration of the stereogenic center bearing the OH group exerts a major influence on the structures of these two peptides; whereas 15 (of unlike-configuration) adopts a 3 14 -helix, the like-configured compound 14 exhibited no helical conformation (NMR investigation [43]). Likewise, peptide 11, which also contains a disubstituted b-amino acid of like-configuration, showed no helical NMR structure, with peptides 12 and 13 assuming the 3 14 -helix [43] [44].…”

“…The configuration of the stereogenic center bearing the OH group exerts a major influence on the structures of these two peptides; whereas 15 (of unlike-configuration) adopts a 3 14 -helix, the like-configured compound 14 exhibited no helical conformation (NMR investigation [43]). Likewise, peptide 11, which also contains a disubstituted b-amino acid of like-configuration, showed no helical NMR structure, with peptides 12 and 13 assuming the 3 14 -helix [43] [44]. Such F-and OH-containing b-peptides have been used for studies aimed at understanding the proteolytic stability of b-peptides [25].…”