Abstract
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.
Highlights
To better understand the conformational properties of the glycan shield covering the surface of the Human Immunodeficiency Virus (HIV) gp120/gp[41] 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
The use of glycosidic (GL) cluster analysis allows for uniquely defining the conformations sampled by the glycans with the analysis of 3D volumes sampled by the glycans and antibodies and overlap coefficients (OC) of those volumes[41, 42], offering insights into the common regions of space sampled by the different moieties
The range of potential interactions between the Env glycans with the CD4 receptor and anti-Env antibodies was determined. These results highlight the potential of MD methods combined with enhanced sampling for probing the structure and dynamics of HIV Env glycoforms in the context of a methodology where the composition of the system can be rigorously defined and studied in molecular detail at biologically relevant temperatures, with the results used in a predictive fashion to facilitate vaccine design
Summary
To better understand the conformational properties of the glycan shield covering the surface of the HIV gp120/gp[41] 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. With the goal of obtaining a better understanding of the conformational properties of the glycan shield of the Env, and the accessibility of the underlying proteins, we undertook a HREX-MD33, 34 study of a glycosylated Env[15] in which the three gp120/gp[41] monomers were differentially glycosylated with high mannose (M5 and M9) glycans (Table S1, supporting information) From this simulation, we obtained a model of substantial glycan conformational heterogeneity, wherein we document the presence of an extensive network of interactions between glycans, with implications for the role of the glycan shield with respect to accessibility of the protein surface to the CD4 receptor, CCR5 and CXCR4 co-receptors, and neutralizing antibodies. These results highlight the potential of MD methods combined with enhanced sampling for probing the structure and dynamics of HIV Env glycoforms in the context of a methodology where the composition of the system can be rigorously defined and studied in molecular detail at biologically relevant temperatures, with the results used in a predictive fashion to facilitate vaccine design
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