Opening dynamics of HIV-1 gp120 upon receptor binding is dictated by a key hydrophobic core
Opening dynamics of HIV-1 gp120 upon receptor binding is dictated by a key hydrophobic core
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HIV-1 gp120 在受体结合后的开放动力学由关键的疏水核心决定
DOI：
10.1039/c9cp04613e
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发表时间：
2019
影响因子：
3.3
通讯作者：
Mengna Lin
中科院分区：
文献类型：
--
作者：
Lin-Tai Da;Mengna Lin
HIV-1的进入首先通过病毒糖蛋白gp 120与宿主T细胞上的其受体CD 4之间的分子识别来介导。gp 120作为中和抗体靶向的关键抗原，其结构特性和与受体结合后的构象动力学一直是研究的热点。然而，CD 4激活的gp 120开放动力学的原子级启示仍然是未知的。在这里，通过构建基于数百个分子动力学（MD）模拟的马尔可夫状态模型（MSM），总模拟时间为1.20微秒（μs），我们确定了gp 120在CD 4结合后的开放动力学过程中的关键亚稳态。MSM提供了一个明确的动态模型，从而确定的亚稳态共存，并可以达到平衡。更重要的是，两侧是可变环（V1、V2和V3）和β20/21区的疏水核心在触发gp 120开放中起着至关重要的作用。因此，任何引入疏水核心的去稳定化效应都可能促进gp 120转变为开放状态。此外，可变环在完全开放的gp 120中表现出高柔性。特别是，V3区域能够探索闭合和开放构象，即使V1/V2环主要采用开放形式。此外，gp 120中的桥接片层形成可能是由进入的共受体/抗体构象诱导的，因为V1/V2结构是高度异质的，使得桥接片层形成的构象不是最多的状态。我们的研究为深入了解gp 120的动力学特征及其对广泛中和抗体的分子修饰提供了依据，这将指导未来设计更有效的gp 120免疫原的尝试。
HIV-1 entry is mediated firstly by the molecular recognition between the viral glycoprotein gp120 and its receptor CD4 on host T-cells. As a key antigen that can be targeted by neutralizing antibodies, gp120 has been a focus for extensive studies with efforts to understand its structural properties and conformational dynamics upon receptor binding. An atomistic-level revelation of gp120 opening dynamics activated by CD4, however, is still unknown. Here, by constructing a Markov State Model (MSM) based on hundreds of Molecular Dynamics (MD) simulations with an aggregated simulation time of ∼20 microseconds (μs), we identify the key metastable states of gp120 during its opening dynamics upon CD4 binding. The MSM provides a clear dynamic model whereby the identified metastable states coexist and can reach an equilibrium. More importantly, a hydrophobic core flanked by variable loops (V1V2 and V3) and the β20/21 region plays an essential role in triggering the gp120 opening. Any destabilizing effects introduced into the hydrophobic core, therefore, can be expected to promote transition of gp120 to an open state. Moreover, the variable loops demonstrate high flexibilities in fully open gp120. In particular, the V3 region is capable of exploring both closed and open conformations, even with the V1/V2 loops largely adopting an open form. In addition, the bridging sheet formation in gp120 is likely induced by the incoming co-receptor/antibody recognitions, since the V1/V2 structure is highly heterogeneous so that the bridging-sheet formed conformation is not the most populated state. Our studies provide deep insights into the dynamic features of gp120 and its molecular recognitions to the broadly neutralizing antibodies, which guides future attempts to design more effective gp120 immunogens.