CONFORMATIONAL-ANALYSIS OF CYCLIC HEXAPEPTIDES CONTAINING THE D-PRO-L-PRO SEQUENCE TO FIX BETA-TURN POSITIONS

Two cyclic hexapeptides, cyclo(D-Pro-Pro-Gly-Arg-Gly-Asp) (1) and cyclo(D-Pro-Pro-Arg-Gly-Asp-Gly) (2), containing a D-Pro-Pro sequence introduced to define and fix the phase of a two-beta-turn backbone were examined by proton NMR methods. The NMR data were used in constrained distance geometry conformation searches to identify the probable backbone conformations. The conformation searches were conducted using upper and lower bound constraints derived from observed nuclear Overhauser effects (NOEs) involving backbone protons and also using additional lower bound constraints from backbone and beta-proton NOEs judged to be unobserved. The two procedures gave substantially the same results although the dihedral angle ranges were narrower with the additional constraints. In each case, the D-Pro-Pro sequence unequivocally adopted a type II' beta-turn conformation as anticipated and stabilized the second turn across the ring from it. In the case of the Arg-Gly sequence of I, a type II turn was predominant; for the Gly-Asp sequence of 2, structures with type I, II, II', and III turns were all returned by the constrained search, and there were no experimental grounds to suggest a preference.