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

Abstract

Synthetic 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.