HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations
HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations
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DOI：
10.1073/pnas.0508452103
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发表时间：
2006-01-24
影响因子：
11.1
通讯作者：
Simmerling, C
中科院分区：
文献类型：
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作者：
Hornak, V;Okur, A;Simmerling, C
我们报告不受约束的，全原子的分子动力学模拟HIV-1蛋白酶，样品的活性位点皮瓣的大的构象变化。特别地，未配体的蛋白酶经历分别在结合有配体的蛋白酶和未配体的蛋白酶的晶体结构中观察到的"闭合"和"半开放"形式之间的多次转化，包括瓣"旋向"的逆转。"在环脲抑制剂存在下的模拟产生稳定的闭合襟翼。此外，我们观察到几个事件，其中的unliganded蛋白酶的皮瓣打开到一个更大的程度比在晶体结构中观察到的，随后返回到半开放状态。我们的数据强烈支持的假设，unliganded蛋白酶主要人口的半开放构象，封闭和完全开放的结构是一个小组成部分的整体合奏。结果还提供了一个模型的皮瓣打开和关闭，被认为是必不可少的酶功能。
We report unrestrained, all-atom molecular dynamics simulations of HIV-1 protease that sample large conformational changes of the active site flaps. In particular, the unliganded protease undergoes multiple conversions between the "closed" and "semiopen" forms observed in crystal structures of inhibitor-bound and unliganded protease, respectively, including reversal of flap "handedness." Simulations in the presence of a cyclic urea inhibitor yield stable closed flaps. Furthermore, we observe several events in which the flaps of the unliganded protease open to a much greater degree than observed in crystal structures and subsequently return to the semiopen state. Our data strongly support the hypothesis that the unliganded protease predominantly populates the semiopen conformation, with closed and fully open structures being a minor component of the overall ensemble. The results also provide a model for the flap opening and closing that is considered to be essential to enzyme function.