Kinetics and free energy of ligand dissociation using weighted ensemble milestoning
Kinetics and free energy of ligand dissociation using weighted ensemble milestoning
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DOI：
10.1063/5.0021953
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发表时间：
2020-10-21
影响因子：
4.4
通讯作者：
Andricioaei, Ioan
中科院分区：
文献类型：
--
作者：
Ray, Dhiman;Gokey, Trevor;Andricioaei, Ioan
本文考虑了最近发展起来的加权集合里程碑（WEM）方案[D]。雷和I. Andricioaei， J. Chem。并测试其模拟配体-受体解离动力学的能力。物理学报，152,234114（2020）。我们对Na+/Cl-离子对和4-羟基-2-丁酮配体与FK506结合蛋白进行了WEM模拟。作为一个原理证明，我们证明了WEM形式再现了Na+/Cl-离子对解离的时间尺度和从长期传统MD模拟中获得的自由能分布。为了提高用于蛋白质-配体结合动力学和热力学的WEM计算的准确性，我们引入了一种改进的WEM方案，称为带约束释放的加权集合里程碑（WEM- rr），该方案可以在不增加额外计算成本的情况下增加每个里程碑的起点数量。WEM-RR计算得到的配体停留时间和结合自由能与实验和先前的计算结果一致。此外，使用里程碑框架，还可以以较低的计算成本计算绑定时间和速率常数、解离常数和提交者概率。我们还提出了一种分析方法来估计结合速率常数（k(on)），当结合主要是扩散驱动的。我们表明，WEM方法可以有效地计算描述配体-受体结合/解结合的多个实验观察值，是计算机辅助抑制剂设计的一个有希望的候选方法。
We consider the recently developed weighted ensemble milestoning (WEM) scheme [D. Ray and I. Andricioaei, J. Chem. Phys. 152, 234114 (2020)] and test its capability of simulating ligand-receptor dissociation dynamics. We performed WEM simulations on the following host-guest systems: Na+/Cl- ion pair and 4-hydroxy-2-butanone ligand with FK506 binding protein. As a proof of principle, we show that the WEM formalism reproduces the Na+/Cl- ion pair dissociation timescale and the free energy profile obtained from long conventional MD simulation. To increase the accuracy of WEM calculations applied to kinetics and thermodynamics in protein-ligand binding, we introduced a modified WEM scheme called weighted ensemble milestoning with restraint release (WEM-RR), which can increase the number of starting points per milestone without adding additional computational cost. WEM-RR calculations obtained a ligand residence time and binding free energy in agreement with experimental and previous computational results. Moreover, using the milestoning framework, the binding time and rate constants, dissociation constants, and committor probabilities could also be calculated at a low computational cost. We also present an analytical approach for estimating the association rate constant (k(on)) when binding is primarily diffusion driven. We show that the WEM method can efficiently calculate multiple experimental observables describing ligand-receptor binding/unbinding and is a promising candidate for computer-aided inhibitor design.