During viral assembly, the human immunodeficiency virus-1 (HIV-1) surface envelope glycoprotein (Env) interacts with the matrix domain (MA) of the immature Gag polyprotein. The detailed mechanism by which Env-MA is incorporated remains unclear. Here, we performed extensive molecular dynamics (MD) simulations of the ADA.CM.755 ∗ and CH505 HIV-1 Env with immature MA bound in model HIV-1 membrane lipid bilayers to explore the specific interactions between the cytoplasmic tails (CTs) of HIV-1 Env and immature MA as well as the dynamic conformations of its ectodomain in the native viral membrane environment. Currently, there is no structure resolved for HIV-1 Env and MA interactions. First, we placed an immature MA lattice (consisting of four neighboring MA trimers) 20 Å away from the CTs of the ADA.CM.755 ∗ and CH505 Env embedded in a model HIV-1 membrane. Pulling simulations were then carried out to insert the palmitoylation motifs of the immature MA lattice into the inner viral membrane leaflet. Two sets of simulations, including cryo-electron tomography (cryo-ET) density-guided and unbiased conventional MD simulations, were carried out on the two simulation systems of ADA.CM.755 ∗ and CH505 in complex with immature MA in a complex lipid composition mimicking HIV-1 viral membrane. Our density-guided and unbiased MD simulations were highly consistent with each other and explained the experimental cryo-ET densities observed for HIV-1 Env with immature MA bound. The Env CT-MA interactions observed during our simulations were later confirmed by mutagenesis experiments. Furthermore, our MD simulations uncovered differences in the conformations of the gp41 ectodomain helical region 2 (HR2) and membrane proximal-external regions (MPERs) when the HIV-1 Env was embedded in its native membrane environment compared to conformations reported in non-native environments.
Do et al. (Sun,) studied this question.
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