Kinetic Models of Cyclosporin A in Polar and Apolar Environments Reveal Multiple Congruent Conformational States
Kinetic Models of Cyclosporin A in Polar and Apolar Environments Reveal Multiple Congruent Conformational States
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DOI：
10.1021/acs.jcim.6b00251
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发表时间：
2016-08-01
影响因子：
5.6
通讯作者：
Riniker, Sereina
中科院分区：
文献类型：
--
作者：
Witek, Jagna;Keller, Bettina G.;Riniker, Sereina
环肽和肽模拟物通常比典型的药物分子更大和更复杂，其膜渗透性可能受到这些化合物在极性和非极性环境中的构象行为的强烈影响。肽的大小和复杂性通常限制了它们的生物利用度，但已知肽天然产物的例子，如环孢菌素A（CsA），可以通过被动扩散穿过细胞膜。CsA是具有七个甲基化骨架酰胺的十一肽。它的晶体结构显示了一个“封闭的”扭曲的β-折叠片构象与四个分子内氢键，也观察到在核磁共振测量CsA在氯仿中。另一方面，当与其靶亲环蛋白结合时，CsA采用没有分子内氢键的“开放”构象。在这项研究中，我们试图通过分子动力学模拟来采样CsA在氯仿和水中的完整构象空间，以便更好地理解其在这两种环境中的构象行为，并合理化实验观察到的CsA良好的膜渗透性。从10 μ s的分子动力学模拟在每种溶剂中，马尔可夫状态模型被构建来表征亚稳态构象状态。在氯仿中的模型进行比较，核Overhauser效应NMR光谱数据在这项研究中报道，并从文献中。在两种溶剂中的构象景观显示出显着的重叠，但也明显不同的功能。
The membrane permeability of cyclic peptides and peptidomimetics, which are generally larger and more complex than typical drug molecules, is likely strongly influenced by the conformational behavior of these compounds in polar and apolar environments. The size and complexity of peptides often limit their bioavailability, but there are known examples of peptide natural products such as cyclosporin A (CsA) that can cross cell membranes by passive diffusion. CsA is an undecapeptide with seven methylated backbone amides. Its crystal structure shows a "closed" twisted beta-pleated sheet conformation with four intramolecular hydrogen bonds that is also observed in NMR measurements of CsA in chloroform. When binding to its target cyclophilin, on the other hand, CsA adopts an "open" conformation without intramolecular hydrogen bonds. In this study, we attempted to sample the complete conformational space of CsA in chloroform and in water by molecular dynamics simulations in order to better understand its conformational behavior in these two environments and to rationalize the good membrane permeability of CsA observed experimentally. From 10 mu s molecular dynamics simulations in each solvent, Markov state models were constructed to characterize the metastable conformational states. The model in chloroform is compared to nuclear Overhauser effect NMR spectroscopy data reported in this study and taken from the literature. The conformational landscapes in the two solvents show significant overlap but also clearly distinct features.