Organophosphate hydrolases are promising as potential biotherapeutic agents to treat poisoning with pesticides or nerve gases. However, these enzymes often need to be further engineered in order to become useful in practice. One example of such enhancement is the alteration of enantioselectivity of diisopropyl fluorophosphatase (DFPase). Molecular modeling techniques offer a unique opportunity to address this task rationally by providing a physical description of the substrate-binding process. However, DFPase is a metalloenzyme, and correct modeling of metal cations is a challenging task generally coming with a tradeoff between simulation speed and accuracy. Here, we probe several molecular mechanical parameter combinations for their ability to empower long simulations needed to achieve a quantitative description of substrate binding. We demonstrate that a combination of the Amber19sb force field with the recently developed 12-6 Ca²⁺ models allows us to both correctly model DFPase and obtain new insights into the DFP binding process.

中文翻译：

---

探讨不同 Ca2+ 参数对二异丙基氟磷酸酶长时间模拟的适用性

有机磷水解酶有望成为治疗杀虫剂或神经毒气中毒的潜在生物治疗剂。然而，这些酶通常需要进一步改造才能在实践中发挥作用。这种增强的一个例子是二异丙基氟磷酸酶 (DFPase) 的对映选择性的改变。分子建模技术提供了一个独特的机会，通过提供底物结合过程的物理描述来合理地解决这一任务。然而，DFPase 是一种金属酶，金属阳离子的正确建模是一项具有挑战性的任务，通常需要在模拟速度和准确性之间进行权衡。在这里，我们探讨了几种分子力学参数组合，因为它们能够实现对底物结合进行定量描述所需的长时间模拟。²⁺模型使我们能够正确地为 DFPase 建模并获得对 DFP 绑定过程的新见解。