Characterization of the water defect at the HIV-1 gp41 membrane spanning domain in bilayers with and without cholesterol using molecular simulations

Abstract

The membrane spanning domain (MSD) of human immunodeficiency virus 1 (HIV-1) envelope glycoprotein gp41 is important for fusion and infection. We used molecular dynamics (MD) simulations (3.4 μs total) to relate membrane and peptide properties that lead to water solvation of the α-helical gp41 MSD’s midspan arginine in pure dipalmitoylphosphatidylcholine (DPPC) and in 50/50 DPPC/cholesterol membranes. We find that the midspan arginine is solvated by water that penetrates the inner leaflet, leading to a so-called water defect. The water defect is surprisingly robust across initial conditions and membrane compositions, but the presence of cholesterol modulates its behavior in several key ways. In the cholesterol-containing membranes, fluctuations in membrane thickness and water penetration depth are localized near the midspan arginine, and the MSD helices display a tightly regulated tilt angle. In the cholesterol-free membranes, thickness fluctuations are not as strongly correlated to the peptide position and tilt angles vary significantly depending on protein position relative to boundaries between domains of differing thickness. Cholesterol in an HIV-1 viral membrane is required for infection. Therefore, this work suggests that the colocalized water defect and membrane thickness fluctuations in cholesterol-containing viral membranes play an important role in fusion by bringing the membrane closer to a stability limit that must be crossed for fusion to occur.

The Atomic Structure of the HIV-1 gp41 Transmembrane Domain and Its Connection to the Immunogenic Membrane-proximal External Region

“…8B) for functional interaction with the TCR complex (30). Finally, a wedge between MPER-N-TMD and C-TMD helices might enable the formation of water defects in the bilayer as suggested by recent MDS studies (15).…”

“…It is postulated that this interfacial helix is followed by a kink of ϳ90°at Lys-683 to allow insertion of the TMD in a perpendicular orientation. In addition, MDS studies predict conformational flexibility for a membrane-embedded TMD stretch close to the polar Arg-696 (14,15). However, high resolution structural data supporting these models have not been reported yet.…”

“…These studies suggest that inter-chain hydrogen bonds may stabilize membrane-embedded trimers. Molecular dynamics simulation (MDS) studies on monomers revealed potential kinks and/or metastable hinges at or around Arg-696, a residue located near the center of TMD (14,15). According to these calculations, the most stable conformation for TMD would be a complete ␣-helical conformation.…”

Insulin mimetic peptide S371 folds into a helical structure

“…We carried out four metadynamics runs for each peptide (the native insulin B‐chain and S371), the details of which are summarized in Table . We briefly note that metadynamics algorithm has been successfully applied to study a number of conformational sampling problems including peptide‐folding studies in the insulin family …”

All-atom virus simulations

“…Other simulation work on Env has focused on identifying correlated motions that may underlie allosteric communication networks within the protein [48, 47, 49, 50]. The transmembrane domain and fusion peptide of Env have also been extensively investigated with MD simulations to explore conformational variability and membrane interactions, providing insights into the mechanism of membrane fusion [51, 52, 53, 54, 55, 56]. …”