Illustrating the correlations between protein dynamics and glycan shielding of HIV-1 Env gp160

The HIV Env glycoprotein gp160 located on the virion surface acts as the first line of interaction with the host and is therefore the primary antigen to trigger immune response. Dense glycosylation on the Env is an evasion strategy used by the virus to physically shield against antibody binding. Previous studies by this group have revealed the global topological features of the glycan shield over a static protein surface. Our current research builds upon the previous findings by investigating how the presence of these glycans as well as the type of glycosylation patterns affect the stability, large-scale dynamics, and subsequently, the function of the glycoprotein. We have performed exhaustive atomistic molecular dynamics simulations on three distinct HIV-1 Env protein systems with (i) a non-glycosylated structure, (ii) full-length 9-mannose, and (iii) native glycosylation patterns respectively, followed by large-scale dimension reduction analyses of backbone motions. Presence of glycans leads to conformational sampling distinct from the unglycosylated protein, stemming from the stabilized hypervariable loops. These collective motions indicate a combination of symmetric ‘blooming’ and a previously observed asymmetric ‘scissoring’ of the trimer, which are further modulated by the glycans. Dynamic cross correlations shed light on possible allosteric modulations at putative antibody epitopes, where covariant motions at distant sites were found to affect epitope dynamics. These epitope exposures were further investigated with network analysis of the glycan shield topology, and transient variations in antibody access were observed. These findings could be instrumental in improving therapeutics design that can employ this variational shielding information to trigger enhanced binding or conformational locking, leading to impeded cellular entry.