Intermolecular β-sheet stabilization with aminopyrazoles
Intermolecular β-sheet stabilization with aminopyrazoles
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DOI：
10.1021/ja972158y
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发表时间：
1997-12-17
影响因子：
15
通讯作者：
Schrader, TH
中科院分区：
文献类型：
--
作者：
Kirsten, CN;Schrader, TH
3-氨基吡唑衍生物是第一个通过纯粹的分子间相互作用稳定N/C-保护二肽中β-折叠构象的人工模板。在复合物中，两个氨基吡唑分子正好位于肽骨架的上方和下方。与肽的顶面结合是非常有利的，因为它同时与受体分子形成三个协同氢键，而底面只有两个。可聚合的3-氨基-和3-酰胺基吡唑已经通过从对甲苯甲酸开始的一般路线以优异的产率获得。与H-1 NMR滴定结合常数为1：1复杂的高达880 M-1已被确定在氯仿中。的缔合常数的强烈影响的氨基吡唑衍生物的电子特性，以及由肽残基的空间需求。变温研究证明了复合物是由动态氢键形成的，并证实了受体分子在顶面的优先结合。通过详细的Karplus-分析的NH-α-CH耦合常数在复杂的二面角θ和络合程度之间的显着的相关性被发现，这表明几个氨基吡唑能够迫使二肽到一个几乎理想的P-折叠构象。在含有甘氨酸的二肽中，第三个氢键使围绕C-C/C-N键的自由旋转减慢到几乎为零。分子内的核Overhauser增强（NOE）提供了额外的证据肽的扩展构象，而强相互分子间NOE给出了存在的关键第三氢键和假定的相互取向的络合合作伙伴的最终证明。第一个H-1 NMR滴定与三肽显示非常有前途的结果，这一概念的应用寡肽。
3-Aminopyrazole derivatives are the first artificial templates that stabilize the beta-sheet conformation in N/C-protected dipeptides by purely intermolecular interactions. In the complex two aminopyrazole molecules lie exactly above and below the peptide backbone. Binding to the top face of the peptide is strongly favored because it forms three cooperative hydrogen bonds simultaneously to the receptor molecule, whereas the bottom face has only two. Polymerizable 3-amino- and 3-amidopyrazoles have been made accessible in excellent yields by a general route starting from p-toluic acid. With H-1 NMR titrations binding constants for the 1:1 complex of up to 880 M-1 have been determined in chloroform. The association constants are strongly influenced by the electronic character of the aminopyrazole derivative as well as by the steric demand of the peptide residues. Variable temperature studies prove that the complex is formed by dynamic hydrogen bonds and confirmed the preferential binding of the receptor molecules at the top face. By detailed Karplus-analysis of the NH-alpha-CH coupling constants in the complex a remarkable correlation between the dihedral angle theta and the degree of complexation was found, which shows that several amidopyrazoles are capable of forcing the dipeptide into an almost ideal P-sheet conformation. In glycine-containing dipeptides the third hydrogen bond slows down the free rotation around the C-C/C-N bond to almost zero. Intramolecular nuclear Overhauser enhancements (NOE) provide additional evidence for the peptide's extended conformation, while strong reciprocal intermolecular NOEs give the final proof of the existence of the critical third hydrogen bond and the postulated mutual orientation of the complexation partners. First H-1 NMR titrations with tripeptides show very promising results concerning the application of this concept to oligopeptides.