HIV-1 Env gp41 Transmembrane Domain Dynamics Are Modulated by Lipid, Water, and Ion Interactions

Abstract

The gp41 transmembrane domain (TMD) of the envelope glycoprotein of the human immunodeficiency virus modulates the conformation of the viral envelope spike, the only druggable target on the surface of the virion. Targeting the envelope glycoprotein with small-molecule and antibody therapies requires an understanding of gp41 TMD dynamics, which is often challenging given the difficulties in describing native membrane properties. Here, atomistic molecular dynamics simulations of a trimeric, prefusion gp41 TMD in a model, asymmetric viral membrane that mimics the native viral envelope were performed. Water and chloride ions were observed to permeate the membrane and interact with the highly conserved arginine bundle, (R696), at the center of the membrane and influenced TMD stability by creating a network of hydrogen bonds and electrostatic interactions. We propose that this (R696) - water - anion network plays an important role in viral fusion with the host cell by modulating protein conformational changes within the membrane. Additionally, R683 and R707 at the exofacial and cytofacial membrane-water interfaces, respectively, are anchored in the lipid headgroup region and serve as a junction point for stabilization of the termini. The membrane thins as a result of the tilting of the gp41 trimer with nearby lipids increasing in volume, leading to an entropic driving force for TMD conformational change. These results provide additional detail and perspective on the influence of certain lipid types on TMD dynamics and a rationale for targeting key residues of the TMD for therapeutic design. These insights into the molecular details of TMD membrane anchoring will build toward a greater understanding of the dynamics that lead to viral fusion with the host cell.

gp120 Alters Its Conformation to Enhance Evasiveness and Infectivity

“…The limited number of residues with little conformational effect on the entire molecule seems to be the major reason for its limited neutralization spectrum. However, the VRC01 binding site is noted to have a conformationally invariant outer domain of gp120 (48,72). It is a good indicator of great neutralizing potential against several HIV-1 strains (48), comprising a large topological area of 1089 Å 2 on the gp120 outer domain, about 50% larger than the 730 Å 2 surfaces utilized by CD4 (112).…”

“…However, the VRC01 binding site is noted to have a conformationally invariant outer domain of gp120 (48,72). It is a good indicator of great neutralizing potential against several HIV-1 strains (48), comprising a large topological area of 1089 Å 2 on the gp120 outer domain, about 50% larger than the 730 Å 2 surfaces utilized by CD4 (112). Table 2 highlights most HIV-1 antibodies and their sites of action in the HIV-1 Env macromolecule.…”

Viral Membrane Fusion and the Transmembrane Domain

“…Molecular dynamic simulations suggest the position of R696 with respect to the membrane leaflets likely plays a role in facilitating the fusion event. R696 can snorkel to interact with the inner leaflet of the membrane, allowing for water penetration into the membrane and membrane thinning needed for membrane fusion [86]. Additional simulations investigated the relationship between cholesterol and R696 [87].…”

“…This concerted action is consistent with R696 snorkeling to the inner membrane leaflet (towards the C-terminus), allowing for membrane perturbations consistent with those needed to facilitate viral entry. There are two additional conserved basic residues (K683 and R707) in the TMD of gp41 [86]. These residues likely interact with the head groups of the outer and inner membrane lipids, respectively.…”

Utilization of computational techniques and tools to introduce or reinforce knowledge of biochemistry and protein structure–function relationships

“…The open pedagogy design approach to UR in biochemistry and utilization of computational techniques reinforces wet‐lab experiences and have been successful in creating meaningful poster presentations and publications. In using this approach, to date, we have supported UR students to present in over 40 poster sessions at 10 different local, national, and international conferences and be authors on 5 peer‐reviewed research articles in notable journals 5–9 . This short communication highlights an open pedagogy design approach to UR in biochemistry and the utilization of computational techniques and tools to both reinforce wet‐lab experiences and provide routes for experiential learning and workforce development when in‐person laboratory work is not feasible.…”