Illuminating the dark conformational space of macrocycles using dominant rotors
Illuminating the dark conformational space of macrocycles using dominant rotors
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DOI：
10.1038/s41557-020-00620-y
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发表时间：
2021-02-15
期刊：
影响因子：
21.8
通讯作者：
Yudin, Andrei K.
中科院分区：
文献类型：
--
作者：
Diaz, Diego B.;Appavoo, Solomon D.;Yudin, Andrei K.
受限分子通常采用一种主要构象，这种限制阻止了对其他能量较低的构象的研究。然而，这些交替的结构可能被证明是有用的，现在已经表明，一个占主导地位的转子方法可以改变肽的能量景观，以创建具有不同构象行为的双阱系统。在室温下可用的热能通常平衡可接近的构象状态。在这里，我们介绍了一种方法，用于隔离独特的和以前研究不足的构象的大环。观察不寻常的构象的16至22元环已成为可能，通过控制它们的相互转化使用占主导地位的转子，这代表可调阻转异构体成分具有相对较高的旋转障碍。密度泛函理论和原位核磁共振测量表明，这里考虑的氨基酸基结构的主要转子候选者应该具有至少25 kcal mol（-1）的旋转能垒。通过NMR光谱和X-射线晶体学确定了大环构象的几何形状的显著差异。有证据表明，氨基酸残基可以被迫进入罕见的转向基序，而不是在相应的线性对应物和同源环中观察到。这些发现将为研究生物活性分子的构象-活性关系开辟新的途径。
Constrained molecules typically adopt one major conformation and this limitation prevents the study of other energetically less-favourable conformations. Nevertheless, these alternate structures might prove to be useful and it has now been shown that a dominant rotor method can alter the energetic landscape of peptides to create two-well systems with distinct conformational behaviour.Three-dimensional conformation is the primary determinant of molecular properties. The thermal energy available at room temperature typically equilibrates the accessible conformational states. Here, we introduce a method for isolating unique and previously understudied conformations of macrocycles. The observation of unusual conformations of 16- to 22-membered rings has been made possible by controlling their interconversion using dominant rotors, which represent tunable atropisomeric constituents with relatively high rotational barriers. Density functional theory and in situ NMR measurements suggest that dominant rotor candidates for the amino-acid-based structures considered here should possess a rotational energy barrier of at least 25 kcal mol(-1). Notable differences in the geometries of the macrocycle conformations were identified by NMR spectroscopy and X-ray crystallography. There is evidence that amino acid residues can be forced into rare turn motifs not observed in the corresponding linear counterparts and homodetic rings. These findings should unlock new avenues for studying the conformation-activity relationships of bioactive molecules.