Unusual Folding Propensity of an Unsubstituted β,γ‐Hybrid Model Peptide: Importance of the CH⋅⋅⋅O Intramolecular Hydrogen Bond

Abstract

The single-crystal X-ray diffraction analysis of a β,γ-hybrid model peptide Boc-β-Ala-γ-Abu-NH2 revealed the existence of four crystallographically independent molecules (A, B, C and D conformers) in the asymmetric unit. The analysis revealed that unusual β-turn-like folded structures predominate, wherein the conformational space of non-proteinogenic β-Ala and γ-Abu residues are restricted to gauche-gauche-skew and skew-gauche-trans-skew orientations, respectively. Interestingly, the U-shaped conformers are seemingly stabilised by an effective unconventional C-H⋅⋅⋅O intramolecular hydrogen bond, encompassing a non-covalent 14-membered ring-motif. Taking into account the signs of torsion angles, these conformers could be grouped into two distinct categories, A/B and C/D, establishing the incidence of non-superimposable stereogeometrical features across a non-chiral one-component peptide model system, that is, "mirror-image-like" relationships. The natural occurrence of β-Ala and γ-Abu entities in various pharmacologically important molecules, coupled with their biocompatibilities, highlight how the non-functionalised β,γ-hybrid segment may offer unique advantages for introducing and/or manipulating a wide spectrum of biologically relevant hydrogen bonded secondary structural mimics in short synthetic peptides.

Anionic CH⋅⋅⋅X−Hydrogen Bonds: Origin of Their Strength, Geometry, and Other Properties

“…[10] For example, the proton donor atom can be less electronegative than the usual O, N, or F atoms. In addition to S or Cl, [11] C has also been shown [12][13][14][15][16][17][18][19][20][21] to participate in H-bonds (HBs) as the proton donor. In an intriguing and initially surprising contradiction of what had appeared to be an ironclad rule, the CÀH stretching frequency of a number of CH···O H-bonds shifts to the blue.…”

The CH‥O H-Bond as a Determining Factor in Molecular Structure

“…Quadrupole couplings and 2 H solution NMR data suggest C α H· · ·O = C HBs in ubiquitin [208]. They have been proposed [209] to act as the principal driving force for folding of β,γ-hybrid model peptide and of the structure of amicyanin [210]. Ultrahigh resolution neutron diffraction data of proteins [211] have noted CH··O HBs with an average HB length of 2.0 Å.…”

Conformation of a terminally protected βγ hybrid dipeptide Boc-Ant-Gpn-OMe stabilized by C6/C7hydrogen bonds

“…1). C-HÁ Á ÁO interactions are also an important determinant of a folded conformation in hybrid peptides (Venugopalan & Kishore, 2013) and crystal packing (Desiraju, 1996;Steiner, 1997;Lo Prestil et al, 2006). The hydrogen-bond parameters are listed in Table 2.…”

“…Recently, an unusal -turn-like structure stabilized by C-HÁ Á ÁO interactions with a 14-membered hydrogen-bonded ring has been reported in an unsubstituted -hybrid peptide, viz. Boc--Ala--Abu-NH 2 (Venugopalan & Kishore, 2013).…”