Understanding of the bridging sheet formation of HIV-1 glycoprotein gp120

As the initial step of the entry of HIV-1 into cells, the interaction of CD4 with gp120 is a central area of concern in HIV-1 biology and intervention studies. CD4 binding induces large conformational changes to gp120, such as the formation of the bridging sheet between the V1/V2 stem and beta20/beta21. Understanding the dynamic process and the mechanism that leads to the formation of the bridging sheet is important. We have studied the formation of the bridging sheet via extensive molecular dynamics simulations on a modeled intermediate state. The intermediate state is derived from the crystal structure of the gp120/CD4 complex with rotation of the alpha1 helix and separation of the V1/V2 stem from beta20/beta21. The molecular dynamics simulations reveal that CD4-bound gp120 leads to the refolding of the bridging sheet but the CD4-free gp120 leads to structures similar to unliganded structures of SIV gp120. The bridging sheet refolds with the S375W mutant, but it does not refold with the W112A and S375W/T257S mutants. Our simulation results are in agreement with experimental observations, and they reveal the importance of the formation of the hydrophobic core to the conformational change of CD4-induced gp120. Other experimental observations, including variations in the binding entropy in different mutants, are also qualitatively reproduced.