Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: Successful in silico prediction of the relative permeabilities of cyclic peptides
Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: Successful in silico prediction of the relative permeabilities of cyclic peptides
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DOI：
10.1021/ja063076p
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发表时间：
2006-11-01
影响因子：
15
通讯作者：
Jacobson, Matthew P.
中科院分区：
文献类型：
--
作者：
Rezai, Taha;Bock, Jonathan E.;Jacobson, Matthew P.
我们报告了环肽被动膜渗透性的原子物理模型。计算建模在实验之前进行，并且不涉及使用“训练数据”。该模型明确对待的肽的构象灵活性，广泛的构象采样在低（膜）和高（水）介电环境。被动膜渗透性的11个环肽的实验获得使用平行的人工膜渗透性测定（PAMPA），并显示出与计算结果的线性相关性与R-2 = 0.96。在一般情况下，结果支持的假设，已经在文献中建立，形成内部氢键的能力是被动膜渗透性的关键，可以是密切相关的化合物，如这里研究的区别因素。然而，我们已经发现，内部氢键的数量，可以形成在膜和溶剂暴露的极性表面积与PAMPA渗透性比我们的模型，定量估计溶剂化自由能损失后，从高介电水移动到低介电膜的内部更差。
We report an atomistic physical model for the passive membrane permeability of cyclic peptides. The computational modeling was performed in advance of the experiments and did not involve the use of "training data". The model explicitly treats the conformational flexibility of the peptides by extensive conformational sampling in low (membrane) and high (water) dielectric environments. The passive membrane permeabilities of 11 cyclic peptides were obtained experimentally using a parallel artificial membrane permeability assay (PAMPA) and showed a linear correlation with the computational results with R-2 = 0.96. In general, the results support the hypothesis, already well established in the literature, that the ability to form internal hydrogen bonds is critical for passive membrane permeability and can be the distinguishing factor among closely related compounds, such as those studied here. However, we have found that the number of internal hydrogen bonds that can form in the membrane and the solvent-exposed polar surface area correlate more poorly with PAMPA permeability than our model, which quantitatively estimates the solvation free energy losses upon moving from high-dielectric water to the low-dielectric interior of a membrane.