Insights into the Dynamics of the HIV-1 Env Glycan Shield

Abstract

The glycan shield of the HIV-1 envelope glycoprotein (Env) presents a challenge for the adaptive immune system by effectively shielding the Env-protein surface from potentially neutralizing antibody. HIV-1 Env is one of the most heavily glycosylated proteins known with roughly half of its mass consisting of host derived N-linked glycans. Little is known about the structural dynamics of these N-linked glycans and how they coordinate together to shield the protein surface.We carried out a 2us molecular dynamics simulation of a fully glycosylated atomistic model of the HIV-1 Env trimer. We observed a scissoring movement that lead to an asymmetry in the Env trimer structure. More detailed analysis involving the interactions between glycans using small-world network analysis showed that highly conserved glycans regulate the accessibility of the CD4 binding site. We also observed the formation of microdomains by patches of glycans that remained stable throughout the most of simulation.In conclusion, the molecular dynamics simulation showed that HIV-1 trimer is an asymmetrical structure and that at any given time the protein surface associated with only one CD4 binding site is freely accessible. This accessibility and scissoring may play a role in enabling initial contact of CD4 with Env trimer, which occurs at an asymmetric stoichiometry (1 CD4 per trimer). Overall, the collective behaviour of glycans at the surface of the HIV trimer is likely a factor that needs to be considered for both CD4 interaction, as well as with potentially neutralizing antibody.