CIFDock: A novel CHARMM-based flexible receptor-flexible ligand docking protocol.
CIFDock: A novel CHARMM-based flexible receptor-flexible ligand docking protocol.
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CIFDock：一种新型的基于 CHARMM 的灵活受体-灵活配体对接方案。
DOI：
10.1002/jcc.26759
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发表时间：
2022
影响因子：
3
通讯作者：
Woodcock,HLee
中科院分区：
文献类型：
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作者：
Vankayala,SaiL;Warrensford,LukeC;Pittman,AmandaR;Pollard,BenjaminC;Kearns,FionaL;Larkin,JosephD;Woodcock,HLee
对接研究在当前的药物发现工作流程中起着至关重要的作用。然而，由于配体取样不足、缺乏蛋白质灵活性、评分功能不足（例如，由于金属、辅助因素等）以及难以保留明确的水分子等因素，限制可能经常出现。在此，我们提出了一种新的基于CHARMM的诱导配合对接（CIFDock）工作流程，通过使用全原子力场耦合到增强的采样分子动力学过程，可以绕过这些限制。自导向朗格万动力学模拟用于有效地采样相关配体构象，侧链取向，结晶水位置和活性位点残基运动。通过使用可扩展的旋转体库对侧链方向进行动态采样，进一步增强了蛋白质的灵活性。该过程的步骤包括固定单个组分（例如配体），同时采样其他组分（例如蛋白质活性位点中的残基），从而使复合物适应构象变化。最终，该复合物的所有组分——蛋白质、配体和水——都被同时采样，并且不受SGLD的限制，以捕获任何诱导的配合效应。这个模块化的灵活对接过程使用CHARMM脚本实现自动化，与SLURM数组处理相连接，并并行化以使用所需数量的处理器。我们通过使用由21个药学相关蛋白组成的数据集进行交叉对接研究来验证CIFDock程序。创建了基于CHARMM的SWISSDOCK评分函数的五个变体，以量化最终生成的姿势的结果。获得的结果与商业对接程序数据相当，或者在某些情况下改进。
Docking studies play a critical role in the current workflow of drug discovery. However, limitations may often arise through factors including inadequate ligand sampling, a lack of protein flexibility, scoring function inadequacies (e.g., due to metals, co‐factors, etc.), and difficulty in retaining explicit water molecules. Herein, we present a novel CHARMM‐based induced fit docking (CIFDock) workflow that can circumvent these limitations by employing all‐atom force fields coupled to enhanced sampling molecular dynamics procedures. Self‐guided Langevin dynamics simulations are used to effectively sample relevant ligand conformations, side chain orientations, crystal water positions, and active site residue motion. Protein flexibility is further enhanced by dynamic sampling of side chain orientations using an expandable rotamer library. Steps in the procedure consisting of fixing individual components (e.g., the ligand) while sampling the other components (e.g., the residues in the active site of the protein) allow for the complex to adapt to conformational changes. Ultimately, all components of the complex—the protein, ligand, and waters—are sampled simultaneously and unrestrained with SGLD to capture any induced fit effects. This modular flexible docking procedure is automated using CHARMM scripting, interfaced with SLURM array processing, and parallelized to use the desired number of processors. We validated the CIFDock procedure by performing cross‐docking studies using a data set comprised of 21 pharmaceutically relevant proteins. Five variants of the CHARMM‐based SWISSDOCK scoring functions were created to quantify the results of the final generated poses. Results obtained were comparable to, or in some cases improved upon, commercial docking program data.