Markovian Weighted Ensemble Milestoning (M-WEM): Long-Time Kinetics from Short Trajectories
Markovian Weighted Ensemble Milestoning (M-WEM): Long-Time Kinetics from Short Trajectories
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DOI：
10.1021/acs.jctc.1c00803
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发表时间：
2021-12-15
影响因子：
5.5
通讯作者：
Andricioaei，Ioan
中科院分区：
文献类型：
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作者：
Ray，Dhiman;Stone，Sharon Emily;Andricioaei，Ioan
我们介绍了一种罕见事件的抽样方案，称为马尔可夫加权Ensemble里程碑（M-WEM），它嵌入一个加权合奏框架内的马尔可夫里程碑理论，有效地计算热力学和动力学性质的长时间尺度的生物分子过程从短原子分子动力学模拟。M-WEM测试的Mu miller-Brown势模型，丙氨酸二肽的构象转换，和毫秒时间尺度的蛋白质-配体的结合在胰蛋白酶-苯甲脒复合物。M-WEM不仅可以定量准确地预测这些过程的动力学，而且还允许一个方案沿着沿着额外的自由度重建多维自由能景观，这些自由度不是里程碑式进展坐标的一部分。对于配体-受体系统，实验停留时间，缔合和解离动力学，和结合自由能可以使用M-WEM在几百纳秒的模拟时间内再现，这是目前可用的其他方法的计算成本的一小部分，并且比实验停留时间小接近4个数量级。由于该方法具有计算精度高、计算量小等优点，在药物动力学和基于自由能的计算药物设计中具有潜在的应用前景。
We introduce a rare-event sampling scheme, named Markovian Weighted Ensemble Milestoning (M-WEM), which inlays a weighted ensemble framework within a Markovian milestoning theory to efficiently calculate thermodynamic and kinetic properties of long-time-scale biomolecular processes from short atomistic molecular dynamics simulations. M-WEM is tested on the Müller–Brown potential model, the conformational switching in alanine dipeptide, and the millisecond time-scale protein–ligand unbinding in a trypsin–benzamidine complex. Not only can M-WEM predict the kinetics of these processes with quantitative accuracy but it also allows for a scheme to reconstruct a multidimensional free-energy landscape along additional degrees of freedom, which are not part of the milestoning progress coordinate. For the ligand–receptor system, the experimental residence time, association and dissociation kinetics, and binding free energy could be reproduced using M-WEM within a simulation time of a few hundreds of nanoseconds, which is a fraction of the computational cost of other currently available methods, and close to 4 orders of magnitude less than the experimental residence time. Due to the high accuracy and low computational cost, the M-WEM approach can find potential applications in kinetics and free-energy-based computational drug design.