BPS2026 – Release of the HIV-1 fusion peptide: A key initial step for viral-host membrane fusion, revealed by selective Gaussian-accelerated molecular dynamics simulation

The human immunodeficiency virus-1 (HIV-1) infects human T cells through a membrane fusion process. The first step involves inserting the HIV-1 gp41 fusion peptide (FP) into the host T cell membrane. However, the FP is located in a closed pocket within the HIV-1 gp41 ectodomain (ED), and the triggering mechanism by which the FP exits its closed pocket remains unclear. Here, we employed Gaussian accelerated molecular dynamics (GaMD) and selective ligand GaMD 3.0 (LiGaMD3) methods explore the exit of the FP from its pocket in the HIV-1 gp41 ED. The simulation system was prepared starting from the 5VN3 PDB structure, the cryo-EM model of B41 SOSIP.664 in complex with soluble CD4 and the 17b antibodies. We removed the soluble CD4 and the 17b antibodies from the structure. GaMD and selective LiGaMD3 simulations, with the selective boost applied to all three FPs in the SOSIP trimer, were carried out on the B41 SOSIP to explore the conformational transitions during FP exit.We did not observe the FP exit from its pocket during the GaMD simulations. Meanwhile, our LiGaMD3 simulations captured the necessary conformational transitions required for the FP to exit its closed pocket. In particular, the FP (and FPPR) must first move upward to move away from its interactions with the CC region. The upward movement of the FP (and FPPR) caused the gp120 to move outward, creating freedom for the FP and HR1-HR2 to extend up and initiate the fusion process. The phenomenon observed was consistent with the proposed models for HIV-1 fusion process, in which the co-receptor (including CD4 and CCR5) binding to gp120 would pull the protein outward to initiate the fusion process.