Intramolecular CH···O Hydrogen‐bond mediated stabilization of a Cis‐DPro imide‐bond in a stereocontrolled heterochiral model peptide

Abstract

The X-ray diffraction analysis of a stereocontrolled heterochiral designed model peptide Boc-(D) Pro-Thr-OMe (1) revealed the existence of an unusual folded molecular structure, stabilized via an effective unconventional C---H…O type intramolecular hydrogen-bond, encompassing a noncovalent 12-membered ring-motif. Together with an uncommon type a disposition of the urethane moiety, the tightly folded topology is compounded with a cis-(D) Pro imide-bond. The overall conformation is suggested to be the reminiscent of specific type VI β-turn structures, hitherto, characterized across the Aaa-cis-Pro peptide-bonds in globular proteins and polypeptides. The (13) C NMR spectrum of 1 in an apolar CDCl(3) environment revealed the presence of approximately an equal population of cis and trans isomers unexpectedly, analogous to Pro side-chain, the (13) C NMR chemical-shifts of Thr C(β) -resonance is observed to be sensitive toward cis-trans isomerization. In conjunction with solid-state FT-IR spectral data, we established that a network of complex intermolecular hydrogen-bonds stabilize a self-complementary noncovalent helical hexagonal self-assembly and crystallographic supramolecular aggregate. The results incline us to highlight that the stabilization of cis-(D) Pro peptide-bond in crystalline state may be driven by the favorable energy of formation of an unconventional weak C---H…O intramolecular hydrogen-bond.

“Bridged” n→π* Interactions Can Stabilize Peptoid Helices

“… However, the stabilization of this conformation has also been attributed in part to a Cα–H···OC interaction. , Although such interactions are typically referred to as conventional, purely electrostatic hydrogen bonds, contributions from weak covalent interactions between the amide π system and the Cα–H bond have also been suggested. This same interaction has recently been shown to significantly affect proline cis – trans isomerism in a model peptide . Most importantly, the geometric arrangements of atoms required for this interaction pervade the previously reported solution-phase and solid-state structures of peptoid PPI-like helices and are consistent with NOE spectroscopy data for compound 3o (vide infra). ,, In addition, a thiopeptoid model compound with an N -α-naphthyl side chain has been shown to adopt a similar conformation in the solid state that would facilitate a CαH···SC interaction .…”

“…62 This same interaction has recently been shown to significantly affect proline cis−trans isomerism in a model peptide. 64 Most importantly, the geometric arrangements of atoms required for this interaction pervade the previously reported solution-phase and solid-state structures of peptoid PPI-like helices and are consistent with NOE spectroscopy data for compound 3o (vide infra). 25,31,48 In addition, a thiopeptoid model compound with an N-α-naphthyl side chain has been shown to adopt a similar conformation in the solid state that would facilitate a CαH•••SC interaction.…”

“…Thus, these interactions could potentially be exploited to construct robust PPI-type helices useful in a wide range of applications. Importantly, although the C–H···OC interaction component of the bridged n →π* Ar interaction has previously been observed to affect proline cis - trans isomerism, peptoids and thiopeptoids present a unique opportunity to modulate the strength of this interaction via readily incorporated N -α-chiral aromatic side chains. Although beyond the scope of this study, the intentional disruption of these n →π* Ar interactions might allow other weaker interactions to play a more dominant role in controlling amide/thioamide isomerism, potentially leading to the formation of new structures containing trans -rotamers.…”

Structural significance of hypermodified nucleic acid base hydroxywybutine (OHyW) which occur at 37th position in the anticodon loop of yeast tRNAPhe

“…Additional stabilization is also expected from interactions between O(23)· · ·HC (15) and O(22)· · ·HC (16). Such C O· · ·HC interactions have also been found important in the conformational study of wybutine [21] as well as in case of other molecules [49][50][51][52][53][54][55][56]. The bifurcated hydrogen bonding interactions between HO(16)· · ·O(6)· · ·HC(15) (Fig.…”

Importance of C–H···O Intramolecular Hydrogen Bonding Across a Nonproteinogenic γ-Aminobenzoic Acid Residue: Stabilization of a Flat β-Strand-like Template

“…The compelling evidence for the existence of an unusual β-strand-like molecular template across the γ-Abz residue in 1 is provided primarily from single crystal X-ray diffraction and 1 H NMR spectroscopic analyses. The stabilization of flat molecular structure by two C–H···O intramolecular hydrogen-bonds, i.e., C β i +1 –H···OC i +1 and C δ i +1 –H···OC i interactions, is rather interesting particularly, in the absence of conventional N–H···OC intramolecular hydrogen bonding. ,, The participation of unactivated aromatic C(sp 2 )–H donor to fabricate effective C–H···O interactions is worth emphasizing in view of the fact that the aromatic C(sp 2 )–H donor is reported to be slightly more activated than an unactivated aliphatic C(sp 3 )–H donor. , The structural role played by unactivated C–H donors to fabricate C–H···O intramolecular hydrogen bonds to stabilize biologically relevant folded peptide conformations have been demonstrated in solid crystalline state. , A strong correlation between experimental (ϕ ∼ −170°, ψ ∼ 146°) and theoretical (ϕ ∼ −179°, ψ ∼ 160°) approaches is indeed encouraging for the reason that deduced molecular conformation is the lowest-energy conformer without the influence of crystal packing forces.…”