Toward On-The-Fly Quantum Mechanical/Molecular Mechanical (QM/MM) Docking: Development and Benchmark of a Scoring Function
Toward On-The-Fly Quantum Mechanical/Molecular Mechanical (QM/MM) Docking: Development and Benchmark of a Scoring Function
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DOI：
10.1021/ci5004152
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发表时间：
2014-11-01
影响因子：
5.6
通讯作者：
Roehrig, Ute F.
中科院分区：
文献类型：
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作者：
Chaskar, Prasad;Zoete, Vincent;Roehrig, Ute F.
我们解决的挑战，治疗极化和共价相互作用的对接，通过开发一个混合量子力学/分子力学（QM/MM）评分功能的基础上半经验自洽的电荷密度泛函紧束缚（SCC-DFTB）方法和CHARMM力场。为了在EADock DSS对接算法中对该评分函数进行基准测试，我们创建了一个公开可用的锌金属蛋白质高质量X射线结构数据集（http：//www.molecular-modelling.ch/resources.php）。对于锌结合配体（226个复合物），QM/MM评分与经典评分函数相比，成功率大幅提高（77.0% vs 61.5%），而对于变构配体（55个复合物），成功率保持不变（49.1%）。QM/MM评分显著提高了正确的锌结合几何形状的检测，并将几个重要药物靶点的对接成功率提高了20%以上。经典和QM/MM评分函数的性能均优于AutoDock 4、AutoDock 4 Zn和AutoDock维纳的性能。
We address the challenges of treating polarization and covalent interactions in docking by developing a hybrid quantum mechanical/molecular mechanical (QM/MM) scoring function based on the semiempirical self-consistent charge density functional tight-binding (SCC-DFTB) method and the CHARMM force field. To benchmark this scoring function within the EADock DSS docking algorithm, we created a publicly available dataset of high-quality X-ray structures of zinc metalloproteins (http://www.molecular-modelling.ch/resources.php). For zinc-bound ligands (226 complexes), the QM/MM scoring yielded a substantially improved success rate compared to the classical scoring function (77.0% vs 61.5%), while, for allosteric ligands (55 complexes), the success rate remained constant (49.1%). The QM/MM scoring significantly improved the detection of correct zinc-binding geometries and improved the docking success rate by more than 20% for several important drug targets. The performance of both the classical and the QM/MM scoring functions compare favorably to the performance of AutoDock4, AutoDock4Zn, and AutoDock Vina.