A Novel Approach to the Investigation of Passive Molecular Permeation through Lipid Bilayers from Atomistic Simulations
A Novel Approach to the Investigation of Passive Molecular Permeation through Lipid Bilayers from Atomistic Simulations
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DOI：
10.1021/jp301083h
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发表时间：
2012-07-26
影响因子：
3.3
通讯作者：
Laio, Alessandro
中科院分区：
文献类型：
--
作者：
Ghaemi, Zhaleh;Minozzi, Manuela;Laio, Alessandro
预测药物透过细胞膜的渗透系数（P）在药物发现中是至关重要的。在这里，我们提出了一种方法来计算P的基础上偏置交换元自相关。该方法允许构建从原子模拟模型的渗透明确考虑到不仅是“平凡的”反应坐标，药物的位置沿着方向垂直于脂质膜平面，但也有其他自由度，例如，渗透分子的扭转角，或描述其溶剂化/去溶剂化的变量。这允许导出渗透过程的准确图像，并构建过渡态的详细分子模型，使得合理控制渗透性能成为可能。我们基准这种方法上的渗透乙醇分子通过POPC膜，表明与我们的模型计算的P值与一个长的无偏分子动力学计算的同一系统。
Predicting the permeability coefficient (P) of drugs permeating through the cell membrane is of paramount importance in drug discovery. We here propose an approach for calculating P based on bias exchange metadynamics. The approach allows constructing from atomistic simulations a model of permeation taking explicitly into account not only the "trivial" reaction coordinate, the position of the drug along the direction normal to the lipid membrane plane, but also other degrees of freedom, for example, the torsional angles of the permeating molecule, or variables describing its solvation/desolvation. This allows deriving an accurate picture of the permeation process, and constructing a detailed molecular model of the transition state, making a rational control of permeation properties possible. We benchmarked this approach on the permeation of ethanol molecules through a POPC membrane, showing that the value of P calculated with our model agrees with the one calculated by a long unbiased molecular dynamics of the same system.