Multisecond ligand dissociation dynamics from atomistic simulations
Multisecond ligand dissociation dynamics from atomistic simulations
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DOI：
10.1038/s41467-020-16655-1
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发表时间：
2020-01
影响因子：
16.6
通讯作者：
Steffen Wolf;Benjamin Lickert;Simon A. Bray;G. Stock
中科院分区：
文献类型：
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作者：
Steffen Wolf;Benjamin Lickert;Simon A. Bray;G. Stock
粗粒化的完全原子分子动力学模拟是一个长期的目标，以允许发生在生物相关的时间尺度上的过程的描述。例如，预测蛋白质-配体解结合的途径、速率和限速步骤对于现代药物发现至关重要。为了实现增强的采样，我们进行耗散校正有针对性的分子动力学模拟，产生自由能和摩擦的考虑中的分子过程的配置文件。随后，我们使用这些领域进行温度提升朗之万模拟占所需的动力学发生在多秒的时间尺度及以上。采用溶剂化氯化钠，胰蛋白酶-苯甲脒和热休克蛋白90-抑制剂蛋白-配体复合物的解离作为测试问题，我们重现率从分子动力学模拟和实验的2-20倍，和解离常数的1-4倍。摩擦剖面的分析表明，绑定和未绑定的动态介导的周围的水化壳在所有调查系统的变化。
Coarse-graining of fully atomistic molecular dynamics simulations is a long-standing goal in order to allow the description of processes occurring on biologically relevant timescales. For example, the prediction of pathways, rates and rate-limiting steps in protein-ligand unbinding is crucial for modern drug discovery. To achieve the enhanced sampling, we perform dissipation-corrected targeted molecular dynamics simulations, which yield free energy and friction profiles of molecular processes under consideration. Subsequently, we use these fields to perform temperature-boosted Langevin simulations which account for the desired kinetics occurring on multisecond timescales and beyond. Adopting the dissociation of solvated sodium chloride, trypsin-benzamidine and Hsp90-inhibitor protein-ligand complexes as test problems, we reproduce rates from molecular dynamics simulation and experiments within a factor of 2–20, and dissociation constants within a factor of 1–4. Analysis of friction profiles reveals that binding and unbinding dynamics are mediated by changes of the surrounding hydration shells in all investigated systems.