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All-atom models of the membrane-spanning domain of HIV-1 gp41 from metadynamics
Vamshi K Gangupomu1, Cameron F Abrams
1Department of Chemical and Biological Engineering, Drexel University, Philadelphia, PA, USA.
Abstract:
The 27-residue membrane-spanning domain (MSD) of the HIV-1 glycoprotein gp41 bears conserved sequence elements crucial to the biological function of the virus, in particular a conserved GXXXG motif and a midspan arginine. However, structure-based explanations for the roles of these and other MSD features remain unclear. Using molecular dynamics and metadynamics calculations of an all-atom, explicit solvent, and membrane-anchored model, we study the conformational variability of the HIV-1 gp41 MSD. We find that the MSD peptide assumes a stable tilted α-helical conformation in the membrane. However, when the side chain of the midspan Arg (694) "snorkels" to the outer leaflet of the viral membrane, the MSD assumes a metastable conformation where the highly-conserved N-terminal core (between Lys(681) and Arg(694) and containing the GXXXG motif) unfolds. In contrast, when the Arg(694) side chain snorkels to the inner leaflet, the MSD peptide assumes a metastable conformation consistent with experimental observations where the peptide kinks at Phe(697) to facilitate Arg(694) snorkeling. Both of these models suggest specific ways that gp41 may destabilize viral membrane, priming the virus for fusion with a target cell.
Insights
The HIV-1 gp41 membrane-spanning domain (MSD) adopts different structures based on arginine side chain positioning. This conformational flexibility may destabilize the viral membrane, facilitating cell entry.
Area of Science:
- Structural biology
- Virology
- Computational biophysics
Background:
- The HIV-1 glycoprotein gp41's membrane-spanning domain (MSD) has conserved elements like the GXXXG motif and a midspan arginine.
- The precise structural roles of these elements in viral function are not fully understood.
Purpose of the Study:
- To investigate the conformational variability of the HIV-1 gp41 MSD using computational methods.
- To elucidate the structure-function relationship of conserved motifs within the gp41 MSD.
Main Methods:
- All-atom molecular dynamics and metadynamics simulations.
- Explicit solvent and membrane-anchored models.
- Analysis of peptide conformational changes in response to side chain interactions.
Main Results:
- The gp41 MSD adopts a stable, tilted alpha-helical conformation in the membrane.
- Arg(694) side chain interactions with membrane leaflets induce distinct metastable conformations.
- Unfolding of the N-terminal core occurs when Arg(694) snorkels to the outer leaflet.
- Peptide kinking at Phe(697) facilitates Arg(694) snorkeling to the inner leaflet.
Conclusions:
- The conformational plasticity of the gp41 MSD is influenced by Arg(694) side chain dynamics.
- These structural changes provide a mechanism for gp41 to destabilize the viral membrane.
- This destabilization is a potential prerequisite for HIV-1 fusion with target cells.
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