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Molecular Simulations and Markov State Modeling Reveal Inactive Form of Quorum Sensing Regulator SdiA of Escherichia Coli
IEEE/ACM Transactions on Computational Biology and Bioinformatics ( IF 4.5 ) Pub Date : 2021-04-20 , DOI: 10.1109/tcbb.2021.3074567
Hovakim Grabski , Siranuysh Ginosyan , Susanna Tiratsuyan

Enteropathogenic Escherichia coli remains one of the most important pathogens infecting children and it is one of the main causes of persistent diarrhea worldwide. Enteropathogenic Escherichia coli is capable of forming biofilms. Several E. coli mechanisms are regulated by quorum sensing, including virulence factors and biofilm formation. Quorum sensing is the communication system of bacteria with the ability to respond to chemical molecules known as autoinducers. Suppressor of division inhibitor (SdiA) is a quorum sensing receptor present in enteropathogenic E. coli in humans that detect acyl-homoserine lactone type autoinducers. SdiA receptor can also respond to autoinducers produced by other bacterial species that control cell division and virulence. SdiA is regulated by 1-octanoyl-rac-glycerol, which serves as an energy source, signaling molecule, and substrate for membrane biogenesis. SdiA is a potential target, which can be used as an anti-infectious technique. Current crystallographic structures for virtual screening may not be sufficient for molecular docking. So they are not very predictive, because the structures are in the active form. It has been shown that SdiA protein is not activated without a ligand. Generally, ligands bind to the ligand binding domain of SdiA. We employ Markov modeling and molecular dynamics simulations to understand the behaviour of SdiA protein and find the possible inactive form. We find an unknown conformation after 24 molecular dynamics simulation runs with random initial velocities and Markov state modeling. In summary, using molecular simulations and Markov state modeling, we have obtained an unknown conformation, which is not available in the crystallographic structures of SdiA. This unknown conformation could be the structure of the inactive form without a ligand. The obtained ensemble structures could be used for virtual screening.

中文翻译:

分子模拟和马尔可夫状态建模揭示了大肠杆菌的群体感应调节器 SdiA 的非活动形式

肠致病性 大肠杆菌仍然是感染儿童的最重要病原体之一,也是全球持续性腹泻的主要原因之一。肠致病性大肠杆菌能够形成生物膜。一些大肠杆菌机制受群体感应的调节,包括毒力因子和生物膜形成。群体感应是细菌的通讯系统,能够对称为自诱导剂的化学分子作出反应。分裂抑制剂 (SdiA) 抑制剂是一种存在于肠道致病菌中的群体感应受体检测酰基高丝氨酸内酯型自诱导物的人体大肠杆菌。SdiA 受体还可以对控制细胞分裂和毒力的其他细菌种类产生的自诱导物作出反应。SdiA 受 1-辛酰基-外消旋甘油的调节,它作为能量来源、信号分子和膜生物发生的底物。SdiA 是一种潜在的靶点,可用作抗感染技术。当前用于虚拟筛选的晶体结构可能不足以进行分子对接。所以它们不是很有预测性,因为结构处于活动形式。已经表明,SdiA 蛋白在没有配体的情况下不会被激活。通常,配体与 SdiA 的配体结合域结合。我们采用马尔可夫建模和分子动力学模拟来了解 SdiA 蛋白的行为并找到可能的非活性形式。在以随机初始速度和马尔可夫状态建模运行 24 次分子动力学模拟后,我们发现了一个未知的构象。总之,使用分子模拟和马尔可夫状态建模,我们获得了一个未知的构象,这在 SdiA 的晶体结构中是不可用的。这种未知的构象可能是没有配体的非活性形式的结构。获得的集成结构可用于虚拟筛选。我们获得了一个未知的构象,这在 SdiA 的晶体结构中是不可用的。这种未知的构象可能是没有配体的非活性形式的结构。获得的集成结构可用于虚拟筛选。我们获得了一个未知的构象,这在 SdiA 的晶体结构中是不可用的。这种未知的构象可能是没有配体的非活性形式的结构。获得的集成结构可用于虚拟筛选。
更新日期:2021-04-20
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