Drug Pressure Selected Mutations in HIV-1 Protease Alter Flap Conformations
Drug Pressure Selected Mutations in HIV-1 Protease Alter Flap Conformations
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DOI：
10.1021/ja807531v
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发表时间：
2009-01-21
影响因子：
15
通讯作者：
Fanucci, Gail E.
中科院分区：
文献类型：
--
作者：
Galiano, Luis;Ding, Fangyu;Fanucci, Gail E.
通过分子动力学 (MD) 模拟和脉冲电子顺磁共振 (EPR) 光谱测量距离来表征两种耐药 HIV-1 蛋白酶结构的瓣构象。 MD 模拟准确地重新生成实验确定的距离剖面，并提供 EPR 数据的结构解释。综合分析表明，HIV-1 PR 中皮瓣的平均构象、皮瓣打开和关闭的范围以及皮瓣的灵活性显着不同，因为抗病毒治疗会产生多种突变，这为抑制剂耐药机制提供了结构性见解。
The flap conformations of two drug-resistant HIV-1 protease constructs were characterized by molecular dynamic (MD) simulations and distance measurements with pulsed electron paramagnetic resonance (EPR) spectroscopy. MD simulations accurately regenerate the experimentally determined distance profiles and provide structural interpretations of the EPR data. The combined analyses show that the average conformation of the flaps, the range of flap opening and closing, and the flexibility of the flaps differ markedly in HIV-1 PR as multiple mutations arise in response to antiviral therapy, providing structural insights into the mechanism of inhibitor resistance.