HIV-1 broadly neutralizing antibodies (bnAbs) can neutralize most HIV-1 clades. Certain HIV-1 bnAbs target the highly conserved membrane-proximal external region (MPER) that is located underneath the ectodomain of the gp160 trimer on the surface of the virus. Among all known MPER bnAbs, 10E8 has one of the best neutralization potencies and breadth, which makes it a good reference system for HIV vaccine design. Due to the location of the MPER, interactions between the antibody and viral membrane are inevitable as observed in multiple experimental studies. In addition, the extent to which 10E8 interacts with other parts of gp160 around the MPER has remained unclear. We use all-atom molecular dynamics simulations to comparatively elucidate atomistic-level behaviors of MPER bnAbs including 10E8, DH511.2, and 4E10. Simulation systems consist of the Fab domain bound to the MPER embedded on a virus-mimetic membrane. In another set of simulations, we included the transmembrane (TM) domain of gp41 following the MPER to examine its role in supporting bnAb binding. We found that the distribution of surface charges on the Fab domain affect the Fab orientation through interactions with the charged lipid head groups. The electrostatic interactions, as well as hydrophobic interactions, differ among the bnAbs tested and correlate with their neutralization potency. These results have implications for the mechanisms of bnAb binding, attendant gp160 conformational alterations, neutralization, and potency.
Qiu et al. (Sun,) studied this question.