Binding of Venezuelan Equine Encephalitis Virus Inhibitors to Importin-α Receptors Explored with All-Atom Replica Exchange Molecular Dynamics.
Binding of Venezuelan Equine Encephalitis Virus Inhibitors to Importin-α Receptors Explored with All-Atom Replica Exchange Molecular Dynamics.
复制标题
用全原子复制品交换分子动力学探索委内瑞拉马脑炎病毒抑制剂与输入α受体的结合。
DOI：
10.1021/acs.jpcb.3c00429
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Klimov,DmitriK
中科院分区：
文献类型：
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作者：
Delfing,BryanM;Olson,Audrey;Laracuente,XavierE;Foreman,KennethW;Paige,Mikell;Kehn-Hall,Kylene;Lockhart,Christopher;Klimov,DmitriK
虽然委内瑞拉马脑炎病毒（VEEV）是一种具有流行性爆发能力的威胁生命的病原体，但FDA尚未批准用于人类的VEEV抗病毒药物。VEEV细胞毒性部分归因于VEEV衣壳蛋白、核输入蛋白importin-α和importin-β以及核输出蛋白CRM 1之间形成四聚体复合物，它们一起阻断通过核孔复合物的运输。实验研究已经鉴定了来自CL 6662支架的小分子作为病毒核定位信号（NLS）序列与importin-α结合的潜在抑制剂。然而，对CL 6662抑制的分子机制知之甚少。为了解决这个问题，我们采用全原子复制交换分子动力学模拟来探测，在原子细节，CL 6662配体的结合机制importin-α。考虑了三种配体，包括G281-1485和两种具有不同疏水性的同系物。我们研究了配体结合位姿的分布，它们的位置，以及通过结合相互作用的强度测量的配体特异性。我们发现G281-1485非特异性结合，在整个NLS结合位点没有形成明确的结合位姿。疏水性较低的同源物的结合相对于NLS结合位点变得强烈靶向，但保持非特异性。然而，更疏水的同源物是强特异性结合剂，并且是三种配体中唯一形成明确结合位姿的配体，同时与NLS结合位点部分重叠。在自由能估计的基础上，我们认为，所有三个配体弱竞争与病毒NLS序列结合importin-α在一个明显的妥协，以保持主机NLS结合。我们进一步表明，全原子副本交换结合模拟是一个可行的工具，用于研究配体结合非特异性，而不形成明确的结合姿势。
Although Venezuelan equine encephalitis virus (VEEV) is a life-threatening pathogen with a capacity for epidemic outbreaks, there are no FDA-approved VEEV antivirals for humans. VEEV cytotoxicity is partially attributed to the formation of a tetrameric complex between the VEEV capsid protein, the nuclear import proteins importin-α and importin-β, and the nuclear export protein CRM1, which together block trafficking through the nuclear pore complex. Experimental studies have identified small molecules from the CL6662 scaffold as potential inhibitors of the viral nuclear localization signal (NLS) sequence binding to importin-α. However, little is known about the molecular mechanism of CL6662 inhibition. To address this issue, we employed all-atom replica exchange molecular dynamics simulations to probe, in atomistic detail, the binding mechanism of CL6662 ligands to importin-α. Three ligands, including G281-1485 and two congeners with varying hydrophobicities, were considered. We investigated the distribution of ligand binding poses, their locations, and ligand specificities measured by the strength of binding interactions. We found that G281-1485 binds nonspecifically without forming well-defined binding poses throughout the NLS binding site. Binding of the less hydrophobic congener becomes strongly on-target with respect to the NLS binding site but remains nonspecific. However, a more hydrophobic congener is a strongly specific binder and the only ligand out of three to form a well-defined binding pose, while partially overlapping with the NLS binding site. On the basis of free energy estimates, we argue that all three ligands weakly compete with the viral NLS sequence for binding to importin-α in an apparent compromise to preserve host NLS binding. We further show that all-atom replica exchange binding simulations are a viable tool for studying ligands binding nonspecifically without forming well-defined binding poses.