COMPARISON OF THE EFFECTS OF (2S,3S)-2,3-METHANOMETHIONINE, (2R,3R)-2,3-METHANOMETHIONINE, AND (2R,3R)-2,3-METHANOPHENYLALANINE ON THE CONFORMATIONS OF SMALL PEPTIDES

The goal of this paper is to lay foundations for an understanding of the local conformational effects of 2,3-methanoamino acids on secondary structures. These studies are a necessary preliminary to the anticipated applications of 2,3-methanoamino acids in rational manipulation of peptidomimetic and protein-mimic conformations. Derails of the research described are as follows. Quenched molecular dynamics (QMD) studies have been performed to compare the conformational effects of (2S,3S)-2,3 -methanomethionine (2S,3S-cyclo-M), (2R,3R)-2,3 -methanomethionine (2R,3R-cyclo-M), and (2R,3R)-2,3-methanophenylalanine (2R,3R-cyclo-F) incorporated into small peptide systems. Data generated for F{2R,3R-cyclo-M}RF-NH2 and F{2S,3S-cyclo-M}R{2R,3R-cyclo-F}-NH2 were compared with that previously obtained for F{2S,3S-cyclo-M}RF-NH2 (J. Am. Chem. Sec. 1995, 117, 54). This approach facilitated comparisons between enantiomeric methanoamino acids (2S,3S-cyclo-M and 2R,3R-cyclo-M which have the amine and side chain functions trans-oriented across a cyclopropane) and between cis- and trans-2,3-methanoamino acids (i.e. 2R,3R-cyclo-M and 2R,3R-cyclo-F). To effect this comparison, the local influences of the 2,3-methanoamino acids were visualized and rationalized using phi,psi, dot plots and Newman projections, respectively. For 2S,3S-cyclo-M, the psi constraints caused by the 3-substituent were greater than the corresponding phi restrictions. The fundamental difference between the enantiomers of (E)-2,3-methanomethionine was that psi values for 2S,3S-cyclo-M in the peptidomimetics tended to be more positive than the corresponding torsions for 2R,3R-cyclo-M. For the cis methanolog, 2R,3R-cyclo-F, phi values were more severely affected than psi torsions, unlike the situation outlined for the E-cyclo-M enantiomers. NMR experiments also were performed to determine any conformational biases of F{2R,3R-cyclo-M}RF-NH2 and F{2S,3S-cyclo-M}R{2R,3R-cyclo-F}-NH2 in dimethyl sulfoxide (DMSO) solution. These data were then compared with results from the calculations. Both the NMR and QMD studies indicated that F{2S,3S-cyclo-M}R{2R,3R-cyclo-F}-NH2 had a bias toward a structure with all the side chains oriented on one face of the molecule and all the carbonyl vectors pointing in the opposite direction. Inconsistencies between the NMR and QMD data arose for F{2R,3R-cyclo-M}RF-NH2, i.e. conformers fitting the NMR data could be located in the families of structures generated by the QMD experiments, but they did not appear to be the mast favorable ones in the theoretical approach. It is suggested that these ambiguities could be due to contributions from different conformers with energies relatively close to the global minimum.