Filtering with Electric Field: The Case of E. coli Porins
Filtering with Electric Field: The Case of E. coli Porins
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DOI：
10.1021/acs.jpclett.5b00612
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发表时间：
2015-05-21
影响因子：
5.7
通讯作者：
Ceccarelli, Matteo
中科院分区：
文献类型：
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作者：
Acosta-Gutierrez, Silvia;Scorciapino, Mariano Andrea;Ceccarelli, Matteo
尽管普通细菌孔蛋白作为极性抗生素的主要途径已被证实，但其作用模式的分子细节仍存在争议。利用分子动力学模拟和水作为探针，我们证明了水分子的强有序性，沿扩散轴在横向上有不同的调谐。对不同通道的保留特征和重要差异进行了表征，提出了一个通用的分子过滤模型。本征电场负责水的有序化，(I)过滤那些可以补偿限制区域中偶极排列的熵减少的偶极分子，以及(Ii)可能通过改变逃离限制区域的方向来产生额外的势垒。我们使用两种抗生素，头孢吡肟和头孢噻肟，通过代谢动力学自由能计算来测试这个模型。合理的药物设计应该考虑到这一点，以筛选具有改善渗透性能的分子。
Although the role of general bacterial porins is well established as main pathway for polar antibiotics, the molecular details of their mode-of-action are still under debate. Using molecular dynamics simulations and water as a probe, we demonstrated the strong ordering of water molecules, differently tuned along the axis of diffusion in the transversal direction. Preserved features and important differences were characterized for different channels, allowing to put forward a general model for molecular filtering. The intrinsic electric field, responsible for water ordering, (i) filters those dipolar molecules that can compensate the entropy decrease by dipole alignment in the restricted region and (ii) might create an additional barrier by changing direction when escaping from the restricted region. We tested this model using two antibiotics, cefepime and cefotaxime, through metadynamics free energy calculations. A rational drug design should take this into account for screening molecules with improved permeation properties.