Parametrization of macrolide antibiotics using the force field toolkit.
Parametrization of macrolide antibiotics using the force field toolkit.
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DOI：
10.1002/jcc.24043
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发表时间：
2015-10-15
影响因子：
3
通讯作者：
Gumbart JC
中科院分区：
文献类型：
--
作者：
Pavlova A;Gumbart JC
大环内酯类抗生素是一类重要的靶向细菌核糖体的抗生素。大环内酯类药物的计算机模拟是有限的，因为以前没有为它们开发特定的力场参数。在这里，我们确定CHARMM兼容的力场参数红霉素，阿奇霉素和泰利霉素，使用VMD中的力场工具包插件。由于它们的尺寸很大，必须开发新的方法来参数化它们。确定部分原子电荷的两种方法，从与TIP3P水的相互作用和从静电势，以及几种方法拟合二面角参数进行了测试。通过核糖体中大环内酯类的分子动力学模拟来评估不同参数集的性能，在初始参数的细化后观察到的关键相互作用的维持有明显的改善。基于大环内酯测试的结果，给出了使用ffTK参数化非常大的分子的推荐程序。
Macrolides are an important class of antibiotics that target the bacterial ribosome. Computer simulations of macrolides are limited since specific force field parameters have not been previously developed for them. Here we determine CHARMM-compatible force field parameters for erythromycin, azithromycin and telithromycin, using the Force Field Toolkit plugin in VMD. Because of their large size, novel approaches for parametrizing them had to be developed. Two methods for determining partial atomic charges, from interactions with TIP3P water and from the electrostatic potential, as well as several approaches for fitting the dihedral parameters were tested. The performance of the different parameter sets was evaluated by molecular dynamics simulations of the macrolides in ribosome, with a distinct improvement in maintenance of key interactions observed after refinement of the initial parameters. Based on the results of the macrolide tests, recommended procedures for parametrizing very large molecules using ffTK are given.