University of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.
Center for Vaccine Development, Institute for Global Health, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
Sci Rep. 2017 Jun 30;7(1):4435. doi: 10.1038/s41598-017-04532-9.
To better understand the conformational properties of the glycan shield covering the surface of the HIV gp120/gp41 envelope (Env) trimer, and how the glycan shield impacts the accessibility of the underlying protein surface, we performed enhanced sampling molecular dynamics (MD) simulations of a model glycosylated HIV Env protein and related systems. Our simulation studies revealed a conformationally heterogeneous glycan shield with a network of glycan-glycan interactions more extensive than those observed to date. We found that partial preorganization of the glycans potentially favors binding by established broadly neutralizing antibodies; omission of several specific glycans could increase the accessibility of other glycans or regions of the protein surface to antibody or CD4 receptor binding; the number of glycans that can potentially interact with known antibodies is larger than that observed in experimental studies; and specific glycan conformations can maximize or minimize interactions with individual antibodies. More broadly, the enhanced sampling MD simulations described here provide a valuable tool to guide the engineering of specific Env glycoforms for HIV vaccine design.
为了更好地了解覆盖 HIV gp120/gp41 包膜 (Env) 三聚体表面的聚糖屏蔽的构象特性，以及聚糖屏蔽如何影响底层蛋白质表面的可及性，我们对模型糖基化 HIV Env 蛋白和相关系统进行了增强采样分子动力学 (MD) 模拟。我们的模拟研究揭示了一个构象异构的聚糖屏蔽，其聚糖-聚糖相互作用网络比迄今为止观察到的更为广泛。我们发现，聚糖的部分预组织可能有利于已建立的广泛中和抗体的结合；省略几个特定的聚糖可以增加其他聚糖或蛋白质表面区域对抗体或 CD4 受体结合的可及性；可以与已知抗体相互作用的聚糖数量大于实验研究中观察到的数量；并且特定的聚糖构象可以最大程度或最小程度地与单个抗体相互作用。更广泛地说，这里描述的增强采样 MD 模拟为 HIV 疫苗设计中特定 Env 糖型的工程提供了有价值的工具。
