Bhimareddy Dinesh

Structural characterization of backbone-expanded helices in hybrid peptides: (αγ)n and (αβ)n sequences with unconstrained β and γ homologues of L-Val.

Learning your I±I²I³s: The diversity of hydrogen-bonding patterns in backbone-expanded hybrid helices is shown by crystal-structure determination of several oligomeric peptides (see scheme; C=gray; H=white; O=red; N=blue). C 12 helices were observed in the I±I³ peptide series for n=2-8. In comparison, the I±I± peptide and I±I² peptide sequences show C 10 and mixed C 14/C 15 helices, respectively. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Unconstrained Homooligomeric gamma-Peptides Show High Propensity for C-14 Helix Formation

Monosubstituted γ(4)-residues (γ(4)Leu, γ(4)Ile, and γ(4)Val) form helices even in short homooligomeric sequences. C14 helix formation is established by X-ray diffraction in homooligomeric (γ)n tetra-, hexa- and decapeptide sequences demonstrating the high propensity of γ residues, with proteinogenic side chains, to adopt locally folded conformations.

C12 Helices in Long Hybrid (αγ)n Peptides Composed Entirely of Unconstrained Residues with Proteinogenic Side Chains

Unconstrained γ(4) amino acid residues derived by homologation of proteinogenic amino acids facilitate helical folding in hybrid (αγ)n sequences. The C12 helical conformation for the decapeptide, Boc-[Leu-γ(4)(R)Val]5-OMe, is established in crystals by X-ray diffraction. A regular C12 helix is demonstrated by NMR studies of the 18 residue peptide, Boc-[Leu-γ(4)(R)Val]9-OMe, and a designed 16 residue (αγ)n peptide, incorporating variable side chains. Unconstrained (αγ)n peptides show an unexpectedly high propensity for helical folding in long polypeptide sequences.

Structural characterization of folded and extended conformations in peptides containing γ amino acids with proteinogenic side chains: crystal structures of γn, (αγ)n and γγδγ sequences

The crystal structures of nine peptides containing γ4Val and γ4Leu are described. The short sequences Boc-[γ4(R)Val]2-OMe 1, Boc-[γ4(R)Val]3-NHMe 2 and Boc-γ4(S)Val-γ4(R)Val-OMe 3 adopt extended apolar, sheet like structures. The tetrapeptide Boc-[γ4(R)Val]4-OMe 4 adopts an extended conformation, in contrast to the folded C14 helical structure determined previously for Boc-[γ4(R)Leu]4-OMe. The hybrid αγ sequence Boc-[Ala-γ4(R)Leu]2-OMe 5 adopts an S-shaped structure devoid of intramolecular hydrogen bonds, with both α residues adopting local helical conformations. In sharp contrast, the tetrapeptides Boc-[Aib-γ4(S)Leu]2-OMe 6 and Boc-[Leu-γ4(R)Leu]2-OMe 7 adopt folded structures stabilized by two successive C12 hydrogen bonds. γ4Val residues have also been incorporated into the strand segments of a crystalline octapeptide, Boc-Leu-γ4(R)Val-Val-DPro-Gly-Leu-γ4(R)Val-Val-OMe 8. The γγδγ tetrapeptide containing γ4Val and δ5Leu residues adopts an extended sheet like structure. The hydrogen bonding pattern at γ residues corresponds to an apolar sheet, while a polar sheet is observed at the lone δ residue. The transition between folded and extended structures at γ residues involves a change of the torsion angle from the gauche to the trans conformation about the Cβ–Cα bond.

Syn vs Anti Carboxylic Acids in Hybrid Peptides: Experimental and Theoretical Charge Density and Chemical Bonding Analysis

A comparative study of syn vs anti carboxylic acids in hybrid peptides based on experimental electron density studies and theoretical calculations shows that, in the anti form, all three bond angles surrounding Ccarboxyl of the -COOH group are close to ∼120°, as expected for a C-sp2 atom, whereas in the syn form, the ∠Cα-C(O)-Ohydroxyl angle is significantly smaller by 5-10°. The oxygen atom in the carboxyl group is more electronegative in the anti form, so the polarity of the acidic O-H bond is higher in the anti form compared to the syn form, as observed within the limitations of H atom treatment in X-ray diffraction. Consequently, the investigated anti carboxylic acid forms the strongest O-H···O hydrogen bond among all model compounds. Furthermore, according to natural bond orbital analysis, the oxygen lone pairs are clearly nonequivalent, as opposed to the general notion of hybridization of equivalent sp2 and sp3 lone pairs on carbonyl or hydroxyl oxygen atoms. The hybridization of the lone pairs is directly related to the directionality and strength of hydrogen bonds.