Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, UK.
Department of Computer Science, University of Bristol, Bristol, UK.
Sci Rep. 2013 Dec 20;3:3561. doi: 10.1038/srep03561.
The emergence of a novel H7N9 avian influenza that infects humans is a serious cause for concern. Of the genome sequences of H7N9 neuraminidase available, one contains a substitution of arginine to lysine at position 292, suggesting a potential for reduced drug binding efficacy. We have performed molecular dynamics simulations of oseltamivir, zanamivir and peramivir bound to H7N9, H7N9-R292K, and a structurally related H11N9 neuraminidase. They show that H7N9 neuraminidase is structurally homologous to H11N9, binding the drugs in identical modes. The simulations reveal that the R292K mutation disrupts drug binding in H7N9 in a comparable manner to that observed experimentally for H11N9-R292K. Absolute binding free energy calculations with the WaterSwap method confirm a reduction in binding affinity. This indicates that the efficacy of antiviral drugs against H7N9-R292K will be reduced. Simulations can assist in predicting disruption of binding caused by mutations in neuraminidase, thereby providing a computational 'assay.'
新型 H7N9 禽流感病毒感染人类是一个严重的问题。已获得的 H7N9 神经氨酸酶基因组序列中，有一个位置 292 的精氨酸被赖氨酸取代，这表明药物结合效力可能降低。我们对奥司他韦、扎那米韦和帕拉米韦与 H7N9、H7N9-R292K 和结构相关的 H11N9 神经氨酸酶的结合进行了分子动力学模拟。结果表明，H7N9 神经氨酸酶与 H11N9 结构同源，以相同的方式结合药物。模拟结果表明，R292K 突变以与实验观察到的 H11N9-R292K 类似的方式破坏 H7N9 中的药物结合。用水置换法进行的绝对结合自由能计算证实了结合亲和力的降低。这表明，针对 H7N9-R292K 的抗病毒药物的疗效将会降低。模拟可以帮助预测神经氨酸酶突变引起的结合破坏，从而提供一种计算“检测”方法。
