Department of Chemistry, Center for Scientific Computation, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, Texas, United States of America.
Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, California, United States of America.
PLoS Comput Biol. 2019 Feb 19;15(2):e1006801. doi: 10.1371/journal.pcbi.1006801. eCollection 2019 Feb.
The fungal circadian clock photoreceptor Vivid (VVD) contains a photosensitive allosteric light, oxygen, voltage (LOV) domain that undergoes a large N-terminal conformational change. The mechanism by which a blue-light driven covalent bond formation leads to a global conformational change remains unclear, which hinders the further development of VVD as an optogenetic tool. We answered this question through a novel computational platform integrating Markov state models, machine learning methods, and newly developed community analysis algorithms. Applying this new integrative approach, we provided a quantitative evaluation of the contribution from the covalent bond to the protein global conformational change, and proposed an atomistic allosteric mechanism leading to the discovery of the unexpected importance of A'α/Aβ and previously overlooked Eα/Fα loops in the conformational change. This approach could be applicable to other allosteric proteins in general to provide interpretable atomistic representations of their otherwise elusive allosteric mechanisms.
真菌生物钟光受体 Vivid（VVD）包含一个光敏别构光、氧、电压（LOV）结构域，该结构域经历了一个大的 N 端构象变化。目前尚不清楚蓝光驱动的共价键形成如何导致全局构象变化，这阻碍了 VVD 作为光遗传学工具的进一步发展。我们通过一个新的计算平台集成了马尔可夫状态模型、机器学习方法和新开发的社区分析算法，回答了这个问题。应用这种新的综合方法，我们对共价键对蛋白质全局构象变化的贡献进行了定量评估，并提出了一个原子变构机制，从而发现了 A'α/Aβ 和以前被忽视的 Eα/Fα 环在构象变化中的意外重要性。这种方法通常适用于其他变构蛋白，为它们难以捉摸的变构机制提供可解释的原子表示。
