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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dissociation of an antiviral compound from the internal pocket of human rhinovirus 14 capsid
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Dissociation of an antiviral compound from the internal pocket of human rhinovirus 14 capsid

机译：从人鼻病毒14衣壳的内部口袋中解离抗病毒化合物

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摘要

WIN antiviral compounds bind human rhinovirus, as well as en-terovirus and parechovirus, in an internal cavity located within the viral protein capsid. Access to the buried pocket necessitates deviation from the average viral protein structure identified by crystallography. We investigated the dissociation of WIN 52084 from the pocket in human rhinovirus 14 by using an adiabatic, biased molecular dynamics simulation method. Multiple dissociation trajectories are used to characterize the pathway. WIN 52084 exits between the polypeptide chain near the ends of βC and βH in a series of steps. Small, transient packing defects in the protein are sufficient for dissociation. A number of torsion-angle transitions of the antiviral compound are involved, which suggests that flexibility in antiviral compounds is important for binding. It is interesting to note that dissociation is associated with an increase in the conformational fluctuations of residues never in direct contact with WIN 52084 over the course of dissociation. These residues are N-terminal residues in the viral proteins VP3 and VP4 and are located in the interior of the capsid near the icosahedral 5-fold axis. The observed changes in dynamics may be relevant to structural changes associated with virion uncoating and its inhibition by antiviral compounds.
机译：WIN抗病毒化合物在位于病毒蛋白衣壳内的内腔中与人鼻病毒，肠病毒和副病毒结合。进入隐窝的通道需要偏离通过晶体学鉴定的平均病毒蛋白结构。我们通过使用绝热的，有偏见的分子动力学模拟方法，研究了WIN 52084从人鼻病毒14的口袋中的解离。使用多个解离轨迹来表征路径。 WIN 52084通过一系列步骤在βC和βH末端附近的多肽链之间退出。蛋白质中短暂的短暂包装缺陷足以解离。涉及抗病毒化合物的许多扭转角转变，这表明抗病毒化合物的柔韧性对于结合很重要。有趣的是，解离与在解离过程中从未与WIN 52084直接接触的残基的构象波动增加有关。这些残基是病毒蛋白VP3和VP4中的N末端残基，位于衣壳内部，靠近二十面体5倍轴。观察到的动力学变化可能与病毒体脱膜及其被抗病毒化合物抑制相关的结构变化有关。

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