Fragment molecular orbital (FMO) method is a powerful computational tool for structure-based drug design, in which protein–ligand interactions can be described by the inter-fragment interaction energy (IFIE) and its pair interaction energy decomposition analysis (PIEDA). Here, we introduced a dynamically averaged (DA) FMO-based approach in which molecular dynamics simulations were used to generate multiple protein–ligand complex structures for FMO calculations. To assess this approach, we examined the correlation between the experimental binding free energies and DA-IFIEs of six CDK2 inhibitors whose net charges are zero. The correlation between the experimental binding free energies and snapshot IFIEs for X-ray crystal structures was R² = 0.75. Using the DA-IFIEs, the correlation significantly improved to 0.99. When an additional CDK2 inhibitor with net charge of −1 was added, the DA FMO-based scheme with the dispersion energies still achieved R² = 0.99, whereas R² decreased to 0.32 employing all the energy terms of PIEDA.

中文翻译：

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通过动态平均的基于片段分子轨道的相互作用能预测细胞周期蛋白依赖性激酶2抑制剂的蛋白质-配体结合亲和力

片段分子轨道（FMO）方法是基于结构的药物设计的强大计算工具，其中蛋白质-配体相互作用可以通过片段间相互作用能（IFIE）及其对相互作用能分解分析（PIEDA）来描述。在这里，我们介绍了一种基于动态平均 (DA) FMO 的方法，其中分子动力学模拟用于生成用于 FMO 计算的多个蛋白质-配体复杂结构。为了评估这种方法，我们检查了六种净电荷为零的 CDK2 抑制剂的实验结合自由能和 DA-IFIE 之间的相关性。X 射线晶体结构的实验结合自由能和快照 IFIE 之间的相关性为R ² = 0.75。使用 DA-IFIE，相关性显着提高到 0.99。当添加额外的净电荷为-1 的 CDK2 抑制剂时，具有分散能的基于 DA FMO 的方案仍然达到R ²  = 0.99，而使用 PIEDA 的所有能量项时， R ²降至 0.32。