Length-Dependent Transition from Extended to Folded Shapes in Short Oligomers of an Azetidine-Based α-Amino Acid: The Critical Role of NH···N H-Bonds

Abstract

Hydrogen bonds (H-bonds) are ubiquitous in peptides and proteins and are central to the stabilization of their structures. Inter-residue H-bonds between non-adjacent backbone amide NH and C=O motifs lead to the well-known secondary structures of helices, turns and sheets, but it is recognized that other H-bonding modes may be significant, including the weak intra-residue H-bond (called a C5 H-bond) that implicates the NH and C=O motifs of the same amino acid residue. Peptide model compounds that adopt stable C5 H-bonds are not readily available and the so-called 2.05-helix, formed by successive C5 H-bonds, is an elusive secondary structure. Using a combination of theoretical chemistry and spectroscopic studies in both the gas phase and solution phase, we have demonstrated that derivatives of 3-amino-1-methylazetidine-3-carboxylic acid, Aatc(Me) can form sidechain–backbone N–H···N C6γ H-bonds that accompany—and thereby stabilize—C5 H-bonds. In the capped trimer of Aatc(Me), extended C5/C6γ motifs are sufficiently robust to challenge classical 310-helix formation in solution and the fully-extended 2.05-helix conformer has been characterized in the gas phase. Concurrent H-bonding support for successive C5 motifs is a new axiom for stabilizing the extended backbone secondary structure in short peptides.

trans-3-Benzyloxycarbonylamino-1-methyl-3-(methylcarbamoyl)azetidine-1-oxide

“…We recently prepared 3-amino-1-methylazetidine-3-carboxylic acid, abbreviated as Aatc(Me), and short peptide derivatives thereof [15][16][17]. The derivative Cbz-Aatc(Me)-NHMe 4 appeared to offer a new opportunity to examine the potential stabilization effects of hydrogen bonding in its corresponding N-oxide, so we undertook its preparation and study.…”

“…The relative stability of these compounds with respect to other azetidine N-oxides was rationalized by 6-membered ring intramolecular hydrogen bonds (Figure 1), which was supported by an X-ray diffraction study on a crystal of 1. We recently prepared 3-amino-1-methylazetidine-3-carboxylic acid, abbreviated as Aatc(Me), and short peptide derivatives thereof [15][16][17]. The derivative Cbz-Aatc(Me)- NHMe 4 appeared to offer a new opportunity to examine the potential stabilization effects of hydrogen bonding in its corresponding N-oxide, so we undertook its preparation and study.…”

Conformer‐Selective Photoelectron Circular Dichroism

“…For more than two decades, socalled double resonance experiments have been developed under supersonic jet conditions or in a cryogenic ion trap; they now reach conformer selectivity even in complex molecular systems. [7][8][9] However, these methods are blind to chirality. Various strategies have been explored to add chiral sensitivity, such as complexation with another chiral molecule, [10][11] and methods resting on nonlinear resonant phase-sensitive microwave spectroscopy, [12] or the use of circularly polarized light.…”

Conformer‐Selective Photoelectron Circular Dichroism

“…In contrast, electronic or vibrational spectroscopy experiments conducted in the gas‐phase reach selectivity because of the narrow bandwidth in absorption, which allows selecting a given conformer. For more than two decades, so‐called double resonance experiments have been developed under supersonic jet conditions or in a cryogenic ion trap; they now reach conformer selectivity even in complex molecular systems [7–9] . However, these methods are blind to chirality.…”