Impact of azaproline on amide cis-trans isomerism: conformational analyses and NMR studies of model peptides including TRH analogues.
Impact of azaproline on amide cis-trans isomerism: conformational analyses and NMR studies of model peptides including TRH analogues.
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DOI：
10.1021/ja020994o
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发表时间：
2003-02
影响因子：
15
通讯作者：
Wei-jun Zhang;A. Berglund;J. Kao;J. Couty;M. Gershengorn;G. Marshall
中科院分区：
文献类型：
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作者：
Wei-jun Zhang;A. Berglund;J. Kao;J. Couty;M. Gershengorn;G. Marshall
β-转角是蛋白质和肽中研究得很好的基序。四个残基，在肽链方向上几乎形成完整的180度转弯，定义了β转弯。根据残基i + 1和i + 2的骨架的Phi和Psi扭转角定义了几种类型的β-转角。一种特殊类型的β-转角，即VI型转角，通常在残基i + 2处含有具有顺式酰胺键的脯氨酸。在氮杂氨基酸中，氨基酸的α-碳变为氮。含有氮杂脯氨酸（azPro）的肽已经通过NMR研究显示在晶体和有机溶剂中均优选VI型β-转角。MC/MD模拟使用GB/SA溶剂化模型的水探索的构象偏好的azPro含有肽在水溶液中的系统。azPro的顺式酰胺构象的构象偏好的增加被清楚地看到，但增加的稳定性相对较小的反式构象相比，以前的建议。为了验证计算结果的正确性，我们合成了[azPro（3）]-TRH和[Phe（2），azPro（3）]-TRH，并通过在极性溶剂中的NMR确定了它们的构象偏好以及azPro取代对其生物活性的影响。
The beta-turn is a well-studied motif in both proteins and peptides. Four residues, making almost a complete 180 degree-turn in the direction of the peptide chain, define the beta-turn. Several types of the beta-turn are defined according to Phi and Psi torsional angles of the backbone for residues i + 1 and i + 2. One special type of beta-turn, the type VI-turn, usually contains a proline with a cis-amide bond at residue i + 2. In an aza-amino acid, the alpha-carbon of the amino acid is changed to nitrogen. Peptides containing azaproline (azPro) have been shown to prefer the type VI beta-turn both in crystals and in organic solvents by NMR studies. MC/MD simulations using the GB/SA solvation model for water explored the conformational preferences of azPro-containing peptides in aqueous systems. An increase in the conformational preference for the cis-amide conformer of azPro was clearly seen, but the increased stability was relatively minor with respect to the trans-conformer as compared to previous suggestions. To test the validity of the calculations in view of the experimental data from crystal structures and NMR in organic solvents, [azPro(3)]-TRH and [Phe(2), azPro(3)]-TRH were synthesized, and their conformational preferences were determined by NMR in polar solvents as well as the impact of the azPro substitution on their biological activities.