Understanding of the Bridging Sheet Formation of HIV-1 Glycoprotein gp120
Understanding of the Bridging Sheet Formation of HIV-1 Glycoprotein gp120
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DOI：
10.1021/jp9081239
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发表时间：
2009-10-29
影响因子：
3.3
通讯作者：
Wu, Yun-Dong
中科院分区：
文献类型：
--
作者：
Da, Lin-Tai;Quan, Jun-Min;Wu, Yun-Dong
作为HIV-1进入细胞的第一步，CD4与gp120的相互作用是HIV-1生物学和干预研究中关注的中心领域。CD4结合诱导gp120的大的构象变化，例如在V1/V2茎和β20/β21之间形成桥膜。了解导致桥联片层形成的动态过程和机理是很重要的。我们通过对模拟的中间态进行广泛的分子动力学模拟，研究了桥联结构的形成。中间态来自gp120/CD4复合体的晶体结构，通过旋转α1螺旋和从β20/β21分离出V1/V2。分子动力学模拟表明，与CD4结合的gp120导致桥联膜的重折叠，而不与CD4结合的gp120导致与SIV gp120的未连接结构相似的结构。桥联膜与S375W突变体发生折叠，但与W112A和S375W/T257S突变体不发生折叠。我们的模拟结果与实验观察结果相一致，揭示了疏水核心的形成对CD4诱导的gp120构象变化的重要性。其他实验观察，包括不同突变体中结合熵的变化，也被定性地复制。
As the initial step of the entry of HIV-1 into cells, the interaction of CD4 with gp120 is a central area of concern in HIV-1 biology and intervention studies. CD4 binding induces large conformational changes to gp120, such as the formation of the bridging sheet between the V1/V2 stem and beta 20/beta 21. Understanding the dynamic process and the mechanism that leads to the formation of the bridging sheet is important. We have studied the formation of the bridging sheet via extensive molecular dynamics simulations on a modeled intermediate state. The intermediate state is derived from the crystal structure of the gp120/CD4 complex with rotation of the alpha 1 helix and separation of the V1/V2 stem from beta 20/beta 21. The molecular dynamics simulations reveal that CD4-bound gp120 leads to the refolding of the bridging sheet but the CD4-free gp120 leads to structures similar to unliganded structures of SIV gp120. The bridging sheet refolds with the S375W mutant, but it does not refold with the W112A and S375W/T257S mutants. Our simulation results are in agreement with experimental observations, and they reveal the importance of the formation of the hydrophobic core to the conformational change of CD4-induced gp120. Other experimental observations, including variations in the binding entropy in different mutants, are also qualitatively reproduced.