Multi-Resolution Simulations of HIV Glycan Shield Reveal Mechanistic Aspects of Immune Evasion

Abstract

Dense arrangement of N-glycans on the HIV-1 envelope (Env) protein masks the underlying antigenic surfaces and acts as a shield from the adaptive immune system. In addition, extreme heterogeneity of these glycans makes the Env glycoprotein recalcitrant to structural studies relevant for vaccine design efforts. Here, we have performed extensive atomistic and coarse-grained (CG) molecular dynamics simulations to elucidate the spatio-temporal properties of the glycan shield in conjunction with the associated glycosylation diversity of the Env. We have optimally parameterized different Env glycoforms using a CG model adapted from the MARTINI-2.2 forcefield. This newly developed model, not only captured most of the atomistic findings, but allowed the exploration of the glycosylation patterns over long time scales. This is the first time to our knowledge such a multi-resolution model was built having native glycosylation pattern including both oligomannose and complex glycans. These simulations were combined with an in-house graph-theory based approach to quantify the glycan shielding behavior over microsecond time scales. We find that the glycan network connectivity remains stable when all the glycans are decorated with just oligomannose as often considered in most of the published studies to-date. However, with native glycosylation (decorated with both complex mannose glycans), we find immunologically more relevant results. Some of the glycans reorganize their orientations over time to enhance the shielding over antigenic regions, eventually leading to evasion from antibodies. In addition, in the presence of glycans, large-scale dimension reduction analyses indicate a blooming and twisting motion of the underlying protein as the backbone slightly rearranges towards a more stable glycosylated trimeric Env conformation.