Lemmin Thomas, Soto Cinque, Stuckey Jonathan, Kwong Peter D
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Structure. 2017 Oct 3;25(10):1631-1639.e2. doi: 10.1016/j.str.2017.07.018. Epub 2017 Sep 7.
The trimeric HIV-1-envelope (Env) spike is one of the most glycosylated protein complexes known, with roughly half its mass comprising host-derived N-linked glycan. Here we use molecular dynamics to provide insight into its structural dynamics and into how both protomer and glycan movements coordinate to shield the Env protein surface. A 2-μs molecular dynamics simulation of a fully glycosylated atomistic model of the HIV-1 SOSIP Env trimer revealed a spectrum of protomer-scissoring and trimer-opening movements. Network analysis showed that highly conserved glycans combined with protomer scissoring to restrict access to the binding site of the CD4 receptor. The network property of betweenness centrality appeared to identify whether glycans spread to restrict access or cluster to maintain the high-mannose character of the shield. We also observed stable microdomains comprising patches of glycan, with neutralizing antibodies generally binding at the interface between glycan microdomains. Overall, our results provide a microsecond-based understanding of the Env glycan shield.
三聚体HIV-1包膜（Env）刺突是已知糖基化程度最高的蛋白质复合物之一，其质量约一半由宿主来源的N-连接聚糖组成。在此，我们运用分子动力学来深入了解其结构动力学，以及原体和聚糖运动如何协同作用以保护Env蛋白表面。对HIV-1 SOSIP Env三聚体的完全糖基化原子模型进行的2微秒分子动力学模拟揭示了一系列原体剪切和三聚体打开运动。网络分析表明，高度保守的聚糖与原体剪切相结合，限制了对CD4受体结合位点的 access。介数中心性的网络特性似乎可以确定聚糖是扩散以限制 access 还是聚集以维持保护罩的高甘露糖特性。我们还观察到由聚糖斑块组成的稳定微结构域，中和抗体通常结合在聚糖微结构域之间的界面处。总体而言，我们的结果提供了基于微秒级的对Env聚糖保护罩的理解。
