BPS2026 – More than a shield: Glycans modulate tilting dynamics of the HIV-1 Env glycoprotein

Human immunodeficiency virus type 1 (HIV-1) remains a major global health challenge, with more than 39 million people currently infected and no effective vaccine available. The viral envelope glycoprotein (Env), a heavily glycosylated class I fusion protein, is central to both membrane fusion and immune evasion. While its glycans are often described as a passive barrier to neutralizing antibodies, their structural roles in regulating Env orientation have remained underexplored. Here, we combined multi-microsecond all-atom molecular dynamics simulations with cryo-electron tomography of virus-like particles to investigate the full-length, glycosylated Env in a native-like membrane environment. Our results show that Env undergoes pronounced tilting relative to the membrane plane, a motion facilitated by cooperative interactions of conserved N-linked glycans at positions N88 and N611. Removal of these glycans markedly reduced tilting, underscoring their anchoring function. Tilting transitions were further accommodated by hinge-like flexibility within the membrane-proximal external region (MPER) and the transmembrane domain (TMD). Importantly, tilting enhanced accessibility of the MPER peptide epitope, creating structural opportunities for antibody binding that are otherwise limited by membrane occlusion. Together, these findings establish a dual role for Env glycans as both immune shields and structural regulators. By linking glycan-membrane interactions to Env orientation and epitope accessibility, this work provides mechanistic insight into viral immune evasion and highlights potential strategies for Env-based immunogen design.