Influence of side chain restriction and NH center dot center dot center dot pi interaction on the beta-turn folding modes of dipeptides incorporatingphenylalanine cyclohexane derivatives

We have synthesized the model dipeptides Piv-L-Pro-c(6)Phe-(NHPr)-Pr-i, inc orporating each of the two cis cyclohexane analogues of phenylalanine: (S,S )- and (R,R)-1-amino-2-phenplcyclohexanecarboxylic acid. Their structural a nalysis has been carried out in solution by H-1 NMR and FTIR absorption spe ctroscopy and in the solid state by X-ray diffraction. In weakly polar chlo rinated 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 t o pn-folding. This behavior does not differ significantly from that exhibit ed 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 crystall ine 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-f olded structure under these conditions. Theoretical calculations, supported by the experimental data, indicate that a c(6)Phe-NH to aromatic pi-orbita ls interaction has an important influence on the observed beta-folding pref erences.