Influence of side chain restriction and NH•••π interaction on the β-turn folding modes of dipeptides incorporating phenylalanine cyclohexane derivatives

We have synthesized the model dipeptides Piv-L-Pro-c(6)Phe-(NHPr)-Pr-i, incorporating each of the two cis cyclohexane analogues of phenylalanine: (S,S)- and (R,R)-1-amino-2-phenplcyclohexanecarboxylic acid. Their structural analysis has been carried out in solution by H-1 NMR and FTIR absorption spectroscopy and in the solid state by X-ray diffraction. In weakly polar chlorinated solvents, the (S,S)c(6)Phe-containing dipeptide mainly accommodates a type I beta-turn, whereas the (R,R) residue shows a greater propensity to pn-folding. This behavior does not differ significantly from that exhibited by the analogous dipeptides containing L- and D-Phe. However, the L-Pro-L-Phe sequence has been shown to undergo a beta I-to-beta II transition in the presence of a strong solvating medium, such as DMSO, or in the crystalline state. Interestingly, Piv-L-Pro-(S,S)c(6)PheNH(i)Pr, incorporating its cyclohexane analogue with chi(l) fixed at +60 degrees, retains the beta I-folded structure under these conditions. Theoretical calculations, supported by the experimental data, indicate that a c(6)Phe-NH to aromatic pi-orbitals interaction has an important influence on the observed beta-folding preferences.