The HIV-1 envelope glycoprotein (Env) trimer (gp120/gp41)3 forms the key functional envelope spike and is the target of neutralizing antibodies. The glycoprotein gp41 component mediates the fusion of viral and host cell membranes. In addition to its ectodomain, the membrane-interacting C terminal domain of gp41 plays a crucial role in maintaining the fusogenicity and antigenic characteristics of Env. The membrane-interacting domain of gp41 consists of the highly conserved membrane proximal external region (MPER), which contains epitopes for broadly neutralizing antibodies, the transmembrane domain (TMD), which anchors Env in the membrane and mediates trimer formation, and the cytoplasmic tail (CT) domain, which plays an important role in Env trafficking to HIV-1 assembly sites. Previous experimental studies have extensively characterized the structure of the C-terminal domain of gp41; however, they reported different conformational states of the MPER and TMD. In this study, we used all-atom molecular dynamics simulations to investigate the structure and function of the membrane-interacting domain of gp41 in an HIV-1 mimetic membrane bilayer. The basic residues in the CT domain were found to interact favorably with PIP2, leading to lateral demixing of lipids and the accumulation of PIP2 in the cytofacial leaflet around the CT baseplate. Additionally, analysis based on an artificial intelligence (AI) machine learning based protocol revealed a diverse conformational ensemble of MPER-TMD, consistent with previous experimental observations. The MPER-TMD adopts both helix-turn-helix and extended helical conformations. We propose that the inherent flexibility of the MPER and the N-terminal region of TMD can play an important role in facilitating the late stages of membrane fusion.
Majumder et al. (Wed,) studied this question.