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-Arg-Phe-amide (FMRFa) was performed to compare the conformational bias caused by trans-2,3-methanomethionine and alpha-methylmethionine stereoisomers. The specific compounds studied were {(2S,3S)-cyclo-M} RFa, 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-turn, inverse gamma-turn, and alpha-helical conformations about the cyclo-M residue are accessible to the two F{cyclo-M} RFa stereoisomers. Similar calculations for F{(S)-alpha-MeM} RFa, and F{(R)-alpha-MeM}RFa indicate that the alpha-methylamino acids tend to favor alpha-helical conformations. The nmr data is presented for the four peptidomimetics. Most informative were the rotating frame nuclear Overhauser effect cross 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 gamma-turn and gamma-turn conformations, respectively, whereas F{(S)-alpha-MeM} RFa and F{(R)-alpha-MeM} RFa tend to form partial left- and right-handed helical structures (although energy differences between the two turn structures, and between the two helical structures are likely to be small). It is suggested that the wider NH-C alpha-CO angle of cyclopropane amino acids and their more severe steric requirements around the C beta carbons force the peptidomimetic N- and C-termini into the same region of conformational space. This favors C7 turns in the cyclopropane amino acid series relative to the less constrained alpha-methyl derivatives.