Cosolvent molecular dynamics (MD) simulations are molecular dynamics simulations used to identify preferable locations of small organic fragments on a protein target. Most cosolvent molecular dynamics workflows make use of only water-soluble fragments, as hydrophobic fragments would cause lipophilic aggregation. To date the two approaches that allow usage of hydrophobic cosolvent molecules are to use a low (0.2 M) concentration of hydrophobic probes, with the disadvantage of a lower sampling speed, or to use force field modifications, with the disadvantage of a difficult and inflexible setup procedure. Here we present a third alternative, that does not suffer from low sampling speed nor from cumbersome preparation procedures. We have built an easy-to-use open source command line tool PART (Plumed Automatic Restraining Tool) to generate a PLUMED file handling all intermolecular restraints to prevent lipophilic aggregation. We have compared restrained and unrestrained cosolvent MD simulations, showing that restraints are necessary to prevent lipophilic aggregation at hydrophobic probe concentrations of 0.5 M. Furthermore, we benchmarked PART generated restraints on a test set of four proteins (Factor-Xa, HIV protease, P38 MAP kinase and RNase A), showing that cosolvent MD with PART generated restraints qualitatively reproduces binding features of cocrystallised ligands.

中文翻译：

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使用 Plumed 自动约束工具 (PART) 通过疏水性探针防止共溶剂分子动力学模拟中的亲脂性聚集

共溶剂分子动力学 (MD) 模拟是用于识别蛋白质靶标上小有机片段的优选位置的分子动力学模拟。大多数共溶剂分子动力学工作流程仅使用水溶性片段，因为疏水性片段会导致亲脂性聚集。迄今为止，允许使用疏水性共溶剂分子的两种方法是使用低（0.2 M）浓度的疏水性探针，其缺点是采样速度较低，或者使用力场修改，其缺点是困难且不灵活设置程序。在这里，我们提出了第三种替代方案，它既不受采样速度低的影响，也不受繁琐的准备程序的影响。我们构建了一个易于使用的开源命令行工具 PART（Plumed 自动约束工具）来生成 PLUMED 文件，处理所有分子间约束以防止亲脂性聚集。我们比较了受限制和不受限制的共溶剂 MD 模拟，表明限制对于防止疏水性探针浓度为 0.5 M 时的亲脂性聚集是必要的。此外，我们对四种蛋白质（Factor-Xa、HIV 蛋白酶、P38）测试集上的 PART 生成的限制进行了基准测试MAP 激酶和 RNase A)，表明共溶剂 MD 与 PART 产生的抑制定性地再现了共结晶配体的结合特征。