Burgess K, Li W, Lim D, Moye-Sherman D
Department of Chemistry, Texas A&M University, College Station 77843-3255, USA.
Biopolymers. 1997 Oct 5;42(4):439-53. doi: 10.1002/(SICI)1097-0282(19971005)42:4<439::AID-BIP7>3.0.CO;2-R.
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.
对序列为苯丙氨酸-甲硫氨酸-精氨酸-苯丙氨酸-酰胺（FMRFa）的四种拟肽进行了比较研究，以比较反式-2,3-甲撑甲硫氨酸和α-甲基甲硫氨酸立体异构体引起的构象偏好。所研究的具体化合物为{(2S,3S)-环-M} RFa、F{(2R,3R)-环-M} RFa、F{(S)-α-甲基甲硫氨酸} RFa和F{(R)-α-甲基甲硫氨酸} RFa。基于CHARMm 22的分子模拟表明，两种F{环-M} RFa立体异构体可形成围绕环-M残基的γ-转角、反向γ-转角和α-螺旋构象。对F{(S)-α-甲基甲硫氨酸} RFa和F{(R)-α-甲基甲硫氨酸} RFa进行的类似计算表明，α-甲基氨基酸倾向于形成α-螺旋构象。给出了这四种拟肽的核磁共振数据。最具信息量的是甲硫氨酸替代物近端的NH质子与Cβ氢之间的旋转框架核Overhauser效应交叉峰。总体而言，这些核磁共振数据表明，F{(2S,3S)-环-M} RFa和F{(2R,3R)-环-M} RFa分别优先采用反向γ-转角和γ-转角构象，而F{(S)-α-甲基甲硫氨酸} RFa和F{(R)-α-甲基甲硫氨酸} RFa倾向于形成部分左手和右手螺旋结构（尽管两种转角结构之间以及两种螺旋结构之间的能量差异可能很小）。有人提出，环丙烷氨基酸较宽的NH-Cα-CO角及其在Cβ碳周围更严格的空间要求迫使拟肽的N端和C端进入构象空间的同一区域。相对于限制较少的α-甲基衍生物，这有利于环丙烷氨基酸系列中的C7转角。
