Witek Jagna, Keller Bettina G, Blatter Markus, Meissner Axel, Wagner Trixie, Riniker Sereina
Laboratory of Physical Chemistry, ETH Zürich , Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland.
Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin , Takustrasse 3, 14195 Berlin, Germany.
J Chem Inf Model. 2016 Aug 22;56(8):1547-62. doi: 10.1021/acs.jcim.6b00251. Epub 2016 Jul 19.
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 β-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 μs 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.
环肽和拟肽的膜通透性通常比典型药物分子更大且更复杂，这些化合物在极性和非极性环境中的构象行为可能对其膜通透性有强烈影响。肽的大小和复杂性常常限制其生物利用度，但已知一些肽类天然产物，如环孢素A（CsA），能够通过被动扩散穿过细胞膜。CsA是一种含有七个甲基化主链酰胺的十一肽。其晶体结构显示出一种“封闭”的扭曲β-折叠构象，带有四个分子内氢键，在CsA于氯仿中的核磁共振测量中也观察到这种构象。另一方面，当CsA与其靶标亲环蛋白结合时，它会采用一种没有分子内氢键的“开放”构象。在本研究中，我们试图通过分子动力学模拟对CsA在氯仿和水中的完整构象空间进行采样，以便更好地理解其在这两种环境中的构象行为，并合理解释实验观察到的CsA良好的膜通透性。从在每种溶剂中进行的10微秒分子动力学模拟中，构建了马尔可夫状态模型来表征亚稳态构象状态。将氯仿中的模型与本研究报告并取自文献的核Overhauser效应核磁共振光谱数据进行比较。两种溶剂中的构象图景显示出显著的重叠，但也有明显不同的特征。
