O09_06

Structure and stability of glycan interaction network on the HIV envelope glycoprotein

Suyong RE *

Artificial Intelligence Center for Health and Biomedical Research (ArCHER), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN)
( * E-mail: suyongre@nibiohn.go.jp)

Many glycoproteins and glycolipids are present on the cell surface, playing roles not only in intercellular communication but also in various diseases, including cancer and infections. On the cell surface, numerous glycans are thought to from cluster structures through dynamic association and dissociation, potentially influencing the recognition by receptor proteins. However, there is no experimental method to directly identify these structures, and the concept remains hypothetical.

Here, we focus on the HIV envelope glycoprotein, which is one of the most extensively studied system. The spike proteins of enveloped viruses in general hold a high proportion of high-mannose-type glycans, which are thought to form clusters. These glycan clusters are considered to play a role in binding with lectins and neutralizing antibodies [1], and identifying their shape and stability could aid in the development of drugs targeting glycans. The HIV envelope glycoprotein is an extreme case of this and makes it as a good model to investigate glycan cluster structures. In this work, based on the electron microscopy structure of the trimeric BG505 SOSIP.664, which preserves the native-like HIV envelope structure (PDB ID: 5ACO) [2], a structural model was constructed with a total of 60 glycans (45 of which were high-mannose-type) attached according to the experimental data [3]. Molecular dynamics simulations were performed over microseconds using GENESIS program package [4,5]. The simulations reveal the variety of conformations and interactions of surface glycans. The results show that glycosylation unevenly shields the protein surface and has only a minor impact on protein dynamics, which is consistent with our previous work on the Lassa envelope glycoprotein [6]. Further analysis of the glycan network suggests that high-mannose-type glycans tend to for clusters in the gp120 domain. These cluster structures change when the glycan at N332, critical for binding neutralizing antibodies, is absent. These results suggest that the glycan clusters are potential antibody targets and there are critical glycans that regulate the stability of these clusters.

References:
[1] Pritchard, L. K. et al. Nature Commun. 2015, 6: 7479.
[2] Lee, J. H. et al. Structure 2015, 23: 1943–1951.
[3] Behrens, A-H. et al. Cell Rep. 2016, 14: 2695–2706.
[4] Jung, J.; Mori, T. et al., WIRES Comput. Mol. Sci. 2017, 39: 2193–2206.
[5] Kobayashi, C.; Jung, J. et al. J. Comput. Chem., 2017, 38: 2193–2206.
[6] Re, S.; Mizuguchi, K. J. Phys. Chem. B, 2021, 125:2089-2097.