Theoretical and NMR Conformational Studies of β-Proline Oligopeptides With Alternating Chirality of Pyrrolidine Units

Abstract

Synthetic β-peptides are potential functional mimetics of native α-proteins. A recently developed, novel, synthetic approach provides an effective route to the broad group of β-proline oligomers with alternating patterns of stereogenic centers. Conformation of the pyrrolidine ring, Z/E isomerism of β-peptide bonds, and hindered rotation of the neighboring monomers determine the spatial structure of this group of β-proline oligopeptides. Preferences in their structural organization and corresponding thermodynamic properties are determined by NMR spectroscopy, restrained molecular dynamics and quantum mechanics. The studied β-proline oligopeptides exist in dimethyl sulfoxide solution in a limited number of conformers, with compatible energy of formation and different spatial organization. In the β-proline tetrapeptide with alternating chirality of composing pyrrolidine units, one of three peptide bonds may exist in an E configuration. For the alternating β-proline pentapeptide, the presence of an E configuration for at least of one β-peptide bond is mandatory. In this case, three peptide bonds synchronously change their configurations. Larger polypeptides may only exist in the presence of several E configurations of β-peptide bonds forming a wave-like extended structure.

Molecular Dynamics Investigation of Phenolic Oxidative Coupling Protein Hyp-1 Derived from Hypericum perforatum

“…However, observed after the MD simulation, the distributions reveal interconversion between endo and exo states for Pro16, Pro64, Pro122, and Pro124 (Figure 4) marked by predicted P(χ 1 ) peaks at χ 1 values contrary to those resulting from experimental structure conformation. The high flexibility of the pyrrolidine ring and the dynamic tendency toward rapid endo-exo and vice versa conversion at the Cγ atom was previously confirmed by the analysis of the 1 H NMR spectrum of proline in aqueous solution [88]. Although the Cγ atom in most of Pro residues exists in one of endo-exo conformation for both A and B protein molecules, their P(χ1) distributions show that conversion to energetically preferred χ1 = 30° (endo form) is incomplete.…”

“…This conformational transformation towards lower energy states was expressed by a probability shift from the t to m rotamer and the resulting switch in χ1 preference. In the case of nine Thr molecules from the Hyp-1 sequence, eight residues have a different simulated rotamer with probability shifted significantly from preferred p (49% independent probability) and m (43% of probability) to the least populated of the three The high flexibility of the pyrrolidine ring and the dynamic tendency toward rapid endo-exo and vice versa conversion at the Cγ atom was previously confirmed by the analysis of the 1 H NMR spectrum of proline in aqueous solution [88]. Although the Cγ atom in most of Pro residues exists in one of endo-exo conformation for both A and B protein molecules, their P(χ 1 ) distributions show that conversion to energetically preferred χ 1 = 30 • (endo form) is incomplete.…”

“…The amino acid sequence of the Hyp-1 protein contains seven Pro, three Ser, and two Cys residues in a monomeric state. Proline molecules tend to adopt endo or exo conformation depending on whether displaced γ carbon is located above or below the plane formed by other α, β, δ, and N atoms [88]. Within the Hyp-1 dimer experimental model, seven Cγ-endo and seven Cγ-exo conformations of proline were expected at χ 1 = 30 • and 330 • , respectively.…”

A Pregnane Steroid as the Chiral Auxiliary in 1,3‐Dipolar Azomethine Ylide's Cycloaddition: Asymmetric Synthesis and Anticancer Activity of Novel Hybrid Compounds

“…Following acryloylation of pyrrolidine‐pregnane hybrid compound 6 a afforded acrylamide 7 , which was involved in next cycloaddition step providing formation of β‐dipeptide‐pregnane hybrid compound 8 (Scheme ). Stereogenic centers of the second formed pyrrolidine ring in compound 8 have alternating absolute configurations with respect to the first pyrrolidine unit that was demonstrated by us abundantly on different objects . Final acryloylation led to acrylamide 9 that could covalently modify nucleophilic species in biomacromolecules as well as homologue 7 due to presence of exocyclic electrophilic fragment …”

“…Stereogenic centers of the second formed pyrrolidine ring in compound 8 have alternating absolute configurations with respect to the first pyrrolidine unit that was demonstrated by us abundantly on different objects. [8,[12][13][14]16] Final acryloylation led to acrylamide 9 that could covalently modify nucleophilic species in biomacromolecules as well as homologue 7 due to presence of exocyclic electrophilic fragment. [17] As uterus and mammary gland represent main target tissues for different progestin hormonal agents, we used human cervical epithelioid cancer HeLa cell culture, estradiolstimulated HeLa-estr cell culture and breast carcinoma MCF-7 cell culture for cytotoxicity testing of the novel hybrid molecules.…”