We investigated the dissociation process of tri-N-acetyl-d-glucosamine from hen egg white lysozyme using parallel cascade selection molecular dynamics (PaCS-MD), which comprises cycles of multiple unbiased MD simulations using a selection of MD snapshots as the initial structures for the next cycle. Dissociation was significantly accelerated by PaCS-MD, in which the probability of rare event occurrence toward dissociation was enhanced by the selection and rerandomization of the initial velocities. Although this complex was stable during 1 μs of conventional MD, PaCS-MD easily induced dissociation within 10⁰–10¹ ns. We found that velocity rerandomization enhances the dissociation of triNAG from the bound state, whereas diffusion plays a more important role in the unbound state. We calculated the dissociation free energy by analyzing all PaCS-MD trajectories using the Markov state model (MSM), compared the results to those obtained by combinations of PaCS-MD and umbrella sampling (US), steered MD (SMD) and US, and SMD and the Jarzynski equality, and experimentally determined binding free energy. PaCS-MD/MSM yielded results most comparable to the experimentally determined binding free energy, independent of simulation parameter variations, and also gave the lowest standard errors.

中文翻译：

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平行级联选择分子动力学模拟的蛋白质-配体解离

我们研究的三解离过程Ñ乙酰基d使用并行级联选择分子动力学（PACS-MD），其包括使用选择MD快照作为初始结构的多个无偏MD模拟的周期葡糖胺从鸡蛋白溶菌酶在下一个周期。PaCS-MD显着加速了解离，通过选择初始速度并对其进行了重新随机化，稀有事件发生了向解离的可能性。尽管此复合物在常规MD的1μs内稳定，但PaCS-MD容易在10 ⁰ –10 ¹内引起解离ns。我们发现速度再随机化增强了triNAG从结合状态的解离，而扩散在未结合状态中起着更重要的作用。我们通过使用马尔可夫状态模型（MSM）分析所有PaCS-MD轨迹来计算解离自由能，并将结果与​​通过PaCS-MD和伞形采样（US），导向MD（SMD）和US组合获得的结果进行比较SMD和Jarzynski相等，并通过实验确定了结合自由能。PaCS-MD / MSM产生的结果与实验确定的结合自由能最可比，与模拟参数的变化无关，并且给出的标准误差最低。