论文标题
使用加权集合米的动力学和配体解离的自由能
Kinetics and Free Energy of Ligand Dissociation Using Weighted Ensemble Milestoning
论文作者
论文摘要
我们认为最近开发的加权集合摩尔斯顿(WEM)方案[J.化学物理。 152,234114(2020)],并测试其模拟配体受体解离动力学的能力。我们在以下主机 - 阵线系统上进行了WEM模拟:Na $^+$/Cl $^ - $离子对和4-羟基-2-丁酮(但)具有FK506结合蛋白(FKBP)的配体。作为证明或原则,我们表明WEM形式主义复制了Na $^+$/cl $^ - $ ion对离解分离时间尺度和从长期常规MD模拟获得的自由能曲线。为了提高适用于蛋白质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,称为加权集合Moresteming具有约束释放(WEM-RR),该方案可以增加每个里程碑的起点数量而不增加额外的计算成本。 WEM-RR计算获得了配体停留时间,并与实验和以前的计算结果一致。此外,使用Mirestoning框架,结合时间和速率常数,解离常数和委员会概率也可以以低计算成本计算。我们还提出了一种分析方法,用于估计关联率常数($ k _ {\ text {on}} $),当时绑定主要是扩散驱动的。我们表明,WEM方法可以有效地计算出描述配体 - 受体结合/解开的多个实验性可观察物,并且是计算机辅助抑制剂设计的有前途的候选者。
We consider the recently developed weighted ensemble milestoning (WEM) scheme [J. Chem. Phys. 152, 234114 (2020)], and test its capability of simulating ligand-receptor dissociation dynamics. We performed WEM simulations on the following host-guest systems: Na$^+$/Cl$^-$ ion pair and 4-hydroxy-2-butanone (BUT) ligand with FK506 binding protein (FKBP). As proof or 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 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 constant and the committor probabilities could also be calculated at a low computational cost. We also present an analytical approach for estimating the association rate constant ($k_{\text{on}}$) 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.