Abstract
HIV-1 envelope glycoprotein (Env) is critical for viral fusion and entry into host cells and remains a primary target for vaccine and antiviral drug development. Advances in soluble gp140 trimer design have provided insight into the ectodomain structure and dynamics. However, the membrane-proximal external region (MPER) and transmembrane domain (TMD) are comparatively understudied, and knowledge of the cytoplasmic tail (CT) is virtually absent. Additionally, the ectodomain and TMD have been investigated separately in previous studies. To investigate the trimeric gp120-gp41 as a complete entity and its structural flexibility, we built a full-length model of the gp120-gp41 trimer that is fully glycosylated with N-linked glycans and embedded in a lipid bilayer, and performed all-atom molecular dynamics simulations. Our results show that the ectodomain maintains a rigid internal structure stable in the prefusion state, whereas the intrinsic flexibility of the MPER enables the ectodomain to adopt a range of tilted orientations, potentially enhancing spatial alignment for receptor engagement. The centrally positioned R696 residue in the TMD interacts with lipid headgroups, ions, and the CT residues, resulting in conformational variability in the TMD and perturbations in the surrounding membrane that may facilitate the fusion process. Finally, we demonstrate how simulation trajectories can be leveraged to evaluate the accessibility of antibody epitopes across different regions of the protein.