Unexpected dimerization of a tripeptide comprising a β,γ‐diamino acid

Abstract

Funding information China Scholarship CouncilWe have previously reported the synthesis of enantiopure β,γ-diamino acids and relevant short α/γ-peptide containing such building blocks. Complete nuclear magnetic resonance (NMR) studies, together with molecular modeling, highlighted the ability of a β,γ-diamino acid to induce various intramolecular turns. In this paper, we describe for the first time the formation of a dimeric structure constituted by α/γ/ α-tripeptide and stabilized by intermolecular interactions. A structural model is proposed based on extensive NMR measurements. was observed in both HN and aliphatic regions. Extensive NMR data (nuclear Overhauser effect spectroscopy [NOESY], correlation spectroscopy [COSY], heteronuclear single-quantum correlation spectroscopy [HSQC]) allowed the assignment of proton and carbon resonances, but the absence of long-range NOE correlation implies that no stable folded conformation exists. When performed in CDCl 3and at low concentration, the 1 H NMR spectrum showed a decreased spectral dispersion. However, we noticed that, in a 50-mM solution of tripeptide 3 in CDCl 3 , eight HN peaks were present, corresponding to two populations (ratio: 47/53) interconverting in the slow exchange regime (see supporting information Figure S24). | 2D NMR in CDCl 32D NMR spectroscopies (COSY, NOESY, and 1 H-15 N-HSQC) were then undertaken to allow the complete proton assignment in the HN region. All 2D NMR experiments were performed using a 50-mM solution of tripeptide 3 in CDCl 3 . Exchange correlations were detected in the NOESY spectrum, reflecting the dynamic equilibrium between the two populations (Figure 2, left). Additionally, a significant 15 N chemical shift difference between the amides and the carbamate groups was found in 1 H-15 N HSQC (Figure 2, right), which is consistent with our HN assignments. In addition to severe overlaps, aliphatic FIGURE 7 Rotating frame nuclear Overhauser effects observed in ROESY spectrum of a 200-mM solution of tripeptide 3 in CDCl 3 (400 MHz, 240 K) FIGURE 8 Proposed arrangement for the dimeric structure 6 of 7 WAN ET AL.

Gramicidin‐S‐Inspired Cyclopeptidomimetics as Potent Membrane‐Active Bactericidal Agents with Therapeutic Potential

“…Peptide design . Recently, one of our studies showed that β,γ‐DiAAs are capable of promoting dimerization when incorporated into α/γ‐hybrid tripeptides through extra hydrogen bonds [44] …”

“…Recently, one of our studies showed that β,γ-DiAAs are capable of promoting dimerization when incorporated into α/γ-hybrid tripeptides through extra hydrogen bonds. [44] We thereby questioned whether these short peptides could serve as β-strand mimics in cyclopeptides. Inspired by the GS sequence, we employed the β-turn inducer ' D Phe-Pro' to constrain the dimeric tripeptide at both ends ( Figure 2).…”

Development of Therapeutic Gramicidin S Analogues Bearing Plastic β,γ‐Diamino Acids

“…These findings are reminiscent of our previous results that instead of intra-molecular interaction, inter-molecular H-bonds are formed when (βR,γR)-DiAA 3 is introduced into short peptides. [45] As can be found in Table 2, the 3 J CαH-NH coupling constants of the Leu, Orn and Val (ranging between 8.6 and 9.1 Hz) of GS corresponds to a β-sheet structure. [46] A set of comparable values were calculated in GS6 while not in other analogues, signifying an analogous secondary structure between GS6 and GS.…”