eLife Assessment
In this valuable study, the authors conducted an impressive amount of atomistic simulations with a glycosylated HIV-1 envelope glycoprotein (Env) trimer in a realistic asymmetric lipid bilayer. The aim was to probe how Env transmembrane domain, cytoplasmic tail, and membrane environment influence ectodomain orientation and antibody epitope exposure. The simulations convincingly show that ectodomain motion is dominated by tilting relative to the membrane and explicitly demonstrate the role of membrane asymmetry in modulating the protein conformation and orientation. Additional analyses of the authors' deposited MD trajectories could serve as invaluable extensions of this work to probe, for example, for exposure of cryptic epitopes and potential allosteric coupling.