CONFORMATION-SPECIFIC UV and IR SPECTROSCOPY OF CONFORMATIONALLY CONSTRAINED α\alpha/γ\gamma PEPTIDE FOLDAMERS

Author Institution: Department of Chemistry, Purdue University, West Lafayette, IN 47907, and Department of Chemistry, Graduate School of Science, Hiroshima University, Higashi-Hiroshima, 739-8526, Japan; Department of Chemistry, Purdue University, West Lafayette, IN 47907; Department of Chemistry, University of Wisconsin, Madison, WI 53706Synthetic foldamers composed of heterogeneous backbones offer constructs for building unique secondary structures. $\alpha$/$\gamma$-peptides juxtapose the $\alpha$-amino acid sub-units typical of proteins with $\gamma$-amino sub-units. Gellman and co-workers have developed efficient syntheses of $\alpha$/$\gamma$-peptides that incorporate a cyclohexyl ring constraint at the $\gamma$$^{3}$-$\gamma$$^{4}$ bond to limit backbone torsional mobility, and found that they form helices held together by C=O({\em i})$\cdot$$\cdot$$\cdot$H-N({\em i}+3) H-bonds composing 12-membered rings both in solution and in crystalline form. This talk will present a detailed study of the single-conformation double-resonance UV and IR spectroscopy of Ac-Ala-$\gamma$$_{ACHC}$-NH-benzyl ($\alpha$$\gamma$) and Ac-$\gamma$$_{ACHC}$-Ala-NH-benzyl ($\gamma$$\alpha$) capped peptides, in which $\gamma$$_{ACHC}$ residues are constrained by a {\em cis} cyclohexyl ring at $\gamma$$^{3}$-$\gamma$$^{4}$ bond with an ethyl group at $\gamma$$^{2}$ position. The two $\alpha$$\gamma$ and $\gamma$$\alpha$ peptides have three amide groups that are the minimum length necessary to form a 12-membered H-bond. Conformational assignments were made using the NH stretch, C=O stretch (amide I), and NH bend (amide II) regions of the IR spectrum with the aid of DFT calculations. The double-resonance UV and IR spectroscopy uncovered the presence of 6 conformers for $\alpha$$\gamma$ and 4 conformers for $\gamma$$\alpha$. In the two peptides, three of ten structures incorporate bifurcated double rings made of 12-membered C=O(1)$\cdot$$\cdot$$\cdot$H-N(3) ring, which is the first stage of the 12-helix, and 7- or 9-membered C=O(1)$\cdot$$\cdot$$\cdot$H-N(2) ring via nearest-neighbor interaction. The other seven structures are constructed based on 5-, 7-, and 9-membered nearest-neighbor H-bonds. The similarities and differences between structures observed for the two two $\alpha$$\gamma$ and $\gamma$$\alpha$ peptides will be discussed

Role of Ring-Constrained γ‑Amino Acid Residues in α/γ-Peptide Folding: Single-Conformation UV and IR Spectroscopy

The capped α/γ-peptide foldamers Ac-γ_ACHC-Ala-NH-benzyl (γα) and Ac-Ala-γ_ACHC-NH-benzyl (αγ) were studied in the gas phase under jet-cooled conditions using single-conformation spectroscopy. These molecules serve as models for local segments of larger heterogeneous 1:1 α/γ-peptides that have recently been synthesized and shown to form a 12-helix composed of repeating C12 H-bonded rings both in crystalline form and in solution [Guo, L.; et al. <i>J. Am. Chem. Soc.</i> <b>2009</b>, <i>131</i>, 16018]. The γα and αγ peptide subunits are structurally constrained at the Cβ–Cγ bond of the γ-residue with a <i>cis</i>-cyclohexyl ring and by an ethyl group at the Cα position. These triamides are the minimum length necessary for the formation of the C12 H-bond. Resonant two-photon ionization (R2PI) provides ultraviolet spectra that have contributions from all conformational isomers, while IR-UV hole-burning (IR-UV HB) and resonant ion-dip infrared (RIDIR) spectroscopies are used to record single-conformation UV and IR spectra, respectively. Four and six conformers are identified in the R2PI spectra of the γα and αγ peptides, respectively. RIDIR spectra in the NH stretch, amide I (CO stretch), and amide II (NH bend) regions are compared with the predictions of density functional theory (DFT) calculations at the M05-2X/6-31+G* level, leading to definite assignments for the H-bonding architectures of the conformers. While the C12 H-bond is present in both γα and αγ, C9 rings are more prevalent, with seven of ten conformers incorporating a C9 H-bond involving in the γ-residue. Nevertheless, comparison of the assigned structures of gas-phase γα and αγ with the crystal structures for γα and larger α/γ-peptides reveals that the constrained γ-peptide backbone formed by the C9 ring is structurally similar to that formed by the larger C12 ring present in the 12-helix. These results confirm that the ACHC/ethyl constrained γ-residue is structurally preorganized to play a significant role in promoting C12 H-bond formation in larger α/γ-peptides

Nanofibers from oxazolidi-2-one containing hybrid foldamers: what is the right molecular size?

A series of oligomers of the type Boc-(L-Phe-D-Oxd)n-OBn (Boc = tert-butoxycarbonyl; Oxd = 4-methyl-5carboxy oxazolidin-2-one; Bn = benzyl) were prepared for n = 2-5. The shortest oligomer, Boc-(L-Phe-D-Oxd)2-OBn, aggregates and forms a fiber-like material with an anti-parallel β-sheet struc- ture in which the oligopeptide units are connected to each other by only one intermolecular hydrogen bond. The longer oligomers exhibit structural heterogeneity. They start to organize into secondary structures by the formation of intramolecular hydrogen bonds at the pentamer level. Microscopy and diffraction of the oligomers indicated a crystalline character for only the shorter ones. © 2009 Wiley-VCH Verlag GmbH & Co