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首页> 外文期刊>RSC Advances >Insights into the molecular mechanism underlying CD4-dependency and neutralization sensitivity of HIV-1: a comparative molecular dynamics study on gp120s from isolates with different phenotypes
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Insights into the molecular mechanism underlying CD4-dependency and neutralization sensitivity of HIV-1: a comparative molecular dynamics study on gp120s from isolates with different phenotypes

机译：深入了解HIV-1 CD4依赖性和中和敏感性的分子机制：来自不同表型分离株的gp120s的比较分子动力学研究

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The envelope (Env) of HIV-1 plays critical roles in viral infection and immune evasion. Although structures of prefusion Env have been determined and phenotypes relevant to the CD4 dependency and the neutralization sensitivity for various HIV-1 isolates have been identified, the detailed structural dynamics and energetics underlying these two phenotypes have remained elusive. In this study, two unliganded structural models of gp120, one from the CD4-dependent, neutralization-resistant isolate H061.14 and the other from the CD4-independent, neutralization-sensitive R2 strain, were constructed, and subsequently were subjected to multiple-replica molecular dynamics (MD) simulations followed by free energy landscape (FEL) construction. Comparative analyses of MD trajectories reveal that during simulations R2-gp120 demonstrated larger structural fluctuations/deviations and higher global conformational flexibility than H061.14-gp120. Close comparison of local conformational flexibility shows that some of the structural regions involving direct interactions with gp41 and adjacent gp120 subunits in the context of the closed trimeric Env exhibit significantly higher flexibility in R2-gp120 than in H061.14-gp120, thus likely increasing the probability for R2-Env to open the trimer crown and prime gp41 fusogenic properties without induction by CD4. Collective motions derived from principal component analysis (PCA) reveal that R2-gp120 is prone to spontaneous transition to the neutralization-sensitive CD4-bound state while H061.14-gp120 tends to maintain the neutralization-resistant unliganded state. Finally, comparison between FELs reveals that R2-gp120 has larger conformational entropy, richer conformational diversity, and lower thermostability than H061.14-gp120, thus explaining why R2-gp120 is more structurally unstable and conformationally flexible, and has a higher propensity to transition to the CD4-bound state than H061.14-gp120. The present results reveal that the differences in dynamics and energetics between R2-gp120 and H061.14-gp120 impart Env trimers with distinct capacities to sample different states ( i.e. , R2-Env samples more readily the open state while H061.14-Env is more inclined to maintain the closed state), thus shedding light on the molecular mechanism underlying the HIV-1 phenotype associated with CD4 dependencyeutralization sensitivity.
机译：HIV-1的包膜（Env）在病毒感染和免疫逃逸中起关键作用。虽然已经确定了融合前Env的结构，并且已经确定了与CD4依赖性和对各种HIV-1分离物的中和敏感性有关的表型，但仍不清楚这两种表型的详细结构动力学和能量学。在这项研究中，构建了gp120的两个非配体结构模型，一个来自CD4依赖性中和抗性分离株H061.14，另一个来自非CD4依赖性中和敏感R2菌株，然后对其进行多次-复制分子动力学（MD）模拟，然后进行自由能态（FEL）构建。 MD轨迹的比较分析表明，与H061.14-gp120相比，在仿真过程中R2-gp120表现出更大的结构波动/偏差和更高的整体构象灵活性。局部构象柔韧性的紧密比较表明，在封闭的三聚体Env的背景下，涉及与gp41和相邻gp120亚基直接相互作用的某些结构区域在R2-gp120中的柔韧性明显高于在H061.14-gp120中，因此可能增加了R2-Env打开三聚体冠和未引起CD4诱导的gp41融合特性的概率。从主成分分析（PCA）得出的集体运动表明，R2-gp120易于自发转变为中和敏感的CD4结合状态，而H061.14-gp120则倾向于保持耐中和的未配体状态。最后，FEL之间的比较显示，与H061.14-gp120相比，R2-gp120具有更大的构象熵，更丰富的构象多样性和更低的热稳定性，从而解释了为什么R2-gp120在结构上更不稳定并且在构象上更灵活，并且具有更高的过渡倾向H061.14-gp120的CD4结合状态。目前的结果表明，R2-gp120和H061.14-gp120之间的动力学和能量学差异赋予Env三聚体以不同的能力来采样不同状态（即，R2-Env更容易采样开放状态，而H061.14-Env更倾向于保持关闭状态），从而使人们了解与CD4依赖性/中和敏感性相关的HIV-1表型的分子机制。

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