Department of Physics, University of Toronto, Toronto, ON, Canada.
Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.
Nat Commun. 2024 Apr 15;15(1):3244. doi: 10.1038/s41467-024-47473-4.
Proteins are molecular machines and to understand how they work, we need to understand how they move. New pump-probe time-resolved X-ray diffraction methods open up ways to initiate and observe protein motions with atomistic detail in crystals on biologically relevant timescales. However, practical limitations of these experiments demands parallel development of effective molecular dynamics approaches to accelerate progress and extract meaning. Here, we establish robust and accurate methods for simulating dynamics in protein crystals, a nontrivial process requiring careful attention to equilibration, environmental composition, and choice of force fields. With more than seven milliseconds of sampling of a single chain, we identify critical factors controlling agreement between simulation and experiments and show that simulated motions recapitulate ligand-induced conformational changes. This work enables a virtuous cycle between simulation and experiments for visualizing and understanding the basic functional motions of proteins.
蛋白质是分子机器，为了了解它们的工作原理，我们需要了解它们是如何运动的。新的泵探针时间分辨 X 射线衍射方法为在晶体中以原子细节在生物学相关的时间尺度上引发和观察蛋白质运动提供了途径。然而，这些实验的实际限制要求并行开发有效的分子动力学方法来加速进展并提取意义。在这里，我们建立了用于模拟蛋白质晶体动力学的稳健和准确的方法，这是一个需要仔细注意平衡、环境组成和力场选择的复杂过程。通过对单链进行超过七毫秒的采样，我们确定了控制模拟与实验一致性的关键因素，并表明模拟运动再现了配体诱导的构象变化。这项工作为可视化和理解蛋白质的基本功能运动提供了模拟和实验之间的良性循环。
