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Center for Nonlinear Studies |
AIDS is a global pandemic with more than 36 million people infected world-wide by the causative Human Immunodeficiency Virus (HIV). The HIV viral envelope protein (Env) has a dense glycan (sugar) shield covering much of the protein surface, which is a key adaptation for escape fromantibodies. This immune evasion strategy, along with the fact that the Env are the only viral proteins on the surface of the virus, make themparticularly interesting as major targets for current HIV vaccine efforts. Experimental analyses of these glycan modifications remain extremely challenging due to their structurally heterogeneous and dynamic nature. Moreover, conventional all-atom molecular dynamicssimulations can provide spatio-temporally localized dynamics but suffer from sampling issues. Here, we have developed a high throughput pipeline to generate extensive number of glycoprotein conformations in atomisticdetail, by homology modeling of the protein, an de novo modeling of the glycans using MODELLER suite. This template-free glycan modeling methodoptimizes an energy function given by acombination of CHARMM36 force-field terms and spatial harmonic restraints in Cartesian space. We first validate this integrated approach by generating a robust ensemble of soluble BG505 Env and quantitatively comparing to experimental cryo-EM maps. Further, we make use of graph theory to capture theprecise topological network, discern potential interaction pathways, and identify concerted behavior of the glycans. Quantification of relative centrality of different glycan positions, subnetwork features, and analyses of local communities within the network, have aided incomprehensive global characterization of the glycan shield. Specifically, glycan clustering geometry and network attributes have been utilized to define regions of relative vulnerability on the sugar shield, which can be harnessed for potential vaccine design.
Host: David Métivier