COMPARISONS OF THE CONFORMATIONAL BIASES IMPOSED BY TRANS-2,3-METHANOMETHIONINE AND ALPHA-METHYLMETHIONINE

A comparative study of four peptidomimetics of the sequence Phe-Met-Ar g-Phe-amide (FMRF alpha) was performed to compare the conformational b ias caused by trans-2,3-methanomethionine and alpha-methylmethionine s tereoisomers. The specific compounds studied were F{(2S,3S)-cyclo-M} R Fa, F{(2R,3R)-cyclo-M} RFa, F{(S)-alpha-MeM} RFa, and F{(R)-alpha-MeM} RFa. Molecular simulations based on CHARMm 22 indicate that gamma-tur n, inverse gamma-turn, and alpha-helical conformations about the cyclo -M residue are accessible to the two F{cyclo-M} RFa stereoisomers. Sim ilar calculations for F{(S)-alpha-MEM} RFa, and F{(R)-alpha-MeM} RFa i ndicate that the alpha-methylamino acids tend to favor alpha-helical c onformations. The nmr data is presented for the four peptidomimetics. Most informative were the rotating frame nuclear Overhauser effect cro ss peaks between the NH protons proximal to the methionine surrogates, and the C-beta hydrogens. Overall, these nmr data indicate F{(2S,3S)- cyclo-M} RFa and F{(2R,3R)-cyclo-M} RFa preferentially adopt inverse g amma-turn and gamma-turn conformations, respectively, whereas F{(S)-al pha-MeM} RFa and F{(R)-alpha-MeM} RFa tend to form partial left- and r ight-handed helical structures (although energy differences between th e two turn structures, and between the two helical structures are like ly to be small). It is suggested that the wider NH-C-alpha-CO angle of cyclopropane amino acids and their more severe steric requirements ar ound the C-beta carbons force the peptidomimetic N- and C-termini into the same region of conformational space. This favors C-7 turns in the cyclopropane amino acid series relative to the less constrained alpha -methyl derivatives. (C) 1997 John Wiley & Sons, Inc.