Evaluating thermodynamic integration performance of the new amber molecular dynamics package and assess potential halogen bonds of enoyl-ACP reductase (FabI) benzimidazole inhibitors.
Evaluating thermodynamic integration performance of the new amber molecular dynamics package and assess potential halogen bonds of enoyl-ACP reductase (FabI) benzimidazole inhibitors.
复制标题
DOI：
10.1002/jcc.24274
复制
发表时间：
2016-04-05
影响因子：
3
通讯作者：
Johnson ME
中科院分区：
文献类型：
--
作者：
Su PC;Johnson ME
热力学积分 (TI) 可以在先导化合物优化程序中提供准确的结合自由能见解，但其高昂的计算费用限制了其使用。在为 FabI 抑制剂先导化合物优化程序开发高效、准确的 TI 协议的过程中，我们使用 11 种苯并咪唑抑制剂与土拉弗朗西斯菌烯酰酰基还原酶复合，仔细比较了 TI 与不同的 Amber 分子动力学 (MD) 引擎（sander 和 pmemd）、MD 模拟长度、中间状态和转换步骤的数量以及一步 TI 中的 Lennard-Jones 和 Coulomb Softcore 电位参数。 （FTFabI）。据我们所知，这是第一项在 TI 上广泛测试新 AMBER MD 引擎 pmemd 并比较蛋白质-配体结合系统中单步 TI 中软核电位参数的研究。性能最佳的模型，即单步 pmemd TI，使用 6 种中间态和 1 ns MD 模拟，与我们之前研究中性能最佳的隐式溶剂方法 QM/MM-GBSA（RMSD = 3.00 kcal/mol）相比，与实验结果（RMSD = 0.52 kcal/mol）具有更好的一致性，同时保持相似的效率。简而言之，我们展示了经过优化的 TI 协议，该协议对于 FtFabI 系统来说具有高精度且经济实惠。这种方法可以在针对 FtFabI 的更大规模苯并咪唑支架先导化合物优化中实施。最后，这里的 TI 结果还提供了结构-活性关系的见解，并表明苯并咪唑化合物中的对位卤素可能与 FabI（一种众所周知的有利于卤素键的酶）形成弱卤素键。
Thermodynamic integration (TI) can provide accurate binding free energy insights in a lead optimization program, but its high computational expense has limited its usage. In the effort of developing an efficient and accurate TI protocol for FabI inhibitors lead optimization program, we carefully compared TI with different Amber molecular dynamics (MD) engines (sander and pmemd), MD simulation lengths, the number of intermediate states and transformation steps, and the Lennard-Jones and Coulomb Softcore potentials parameters in the one-step TI, using eleven benzimidazole inhibitors in complex with Francisella tularensis enoyl acyl reductase (FtFabI). To our knowledge, this is the first study to extensively test the new AMBER MD engine, pmemd, on TI and compare the parameters of the Softcore potentials in the one-step TI in a protein-ligand binding system. The best performing model, the one-step pmemd TI, using 6 intermediate states and 1 ns MD simulations, provides better agreement with experimental results (RMSD = 0.52 kcal/mol) than the best performing implicit solvent method, QM/MM-GBSA from our previous study (RMSD = 3.00 kcal/mol), while maintaining similar efficiency. Briefly, we show the optimized TI protocol to be highly accurate and affordable for the FtFabI system. This approach can be implemented in a larger scale benzimidazole scaffold lead optimization against FtFabI. Lastly, the TI results here also provide structure-activity relationship insights, and suggest the para-halogen in benzimidazole compounds might form a weak halogen bond with FabI, which is a well-known halogen bond favoring enzyme.