Molecular Dynamics Investigation of Membrane-Bound Bundles of the Channel-Forming Transmembrane Domain of Viral Protein U from the Human Immunodeficiency Virus HIV-1

Abstract

Molecular dynamics (MD) simulations have been carried out on bundles of the channel-forming transmembrane (TM) domain of the viral protein U (VPU(1-27) and VPU(6-27)) from the human immunodeficiency virus (HIV-1). Simulations of hexameric and pentameric bundles of VPU(6-27) in an octane/water membrane mimetic system suggested that the pentamer is the preferred oligomer. Accordingly, an unconstrained pentameric helix bundle of VPU(1-27) was then placed in a hydrated palmitoyl-oleyl-3-n-glycero-phosphatidylethanolamine (POPE) lipid bilayer and its structural properties calculated from a 3-ns MD run. Some water molecules, initially inside the channel lumen, were expelled halfway through the simulation and the bundle adopted a conical structure reminiscent of previous MD results obtained for VPU(6-27) in an octane/water system. The pore constriction generated may correspond to a closed state of the channel and underlies the relocation of the W residue toward the pore lumen. The relative positions of the helices with respect to the bilayer and their interactions with the lipids are discussed. The observed structure is stabilized via specific interactions between the VPU helices and the carbonyl oxygen atoms of the lipid molecules, particularly at the Q and S residues.

Chemical Synthesis and Single Channel Properties of Tetrameric and Pentameric TASPs (Template-assembled Synthetic Proteins) Derived from the Transmembrane Domain of HIV Virus Protein u (Vpu)

“…The calculated structure (Fig. 2B) agrees fairly well with that derived from Molecular Dynamics simulations (21,22). Significantly, it assigns the location of Trp-22 and Ser-23 at proposed strategic positions for the gating of the channel.…”

Oligomerization state and supramolecular structure of the HIV‐1 Vpu protein transmembrane segment in phospholipid bilayers

“…28 Similar stability is then expected for our model in Figure 13(d). Lopez et al carried out molecular dynamics simulations for a Vpu TM pentamer with allatom representations of the phospholipid bilayer and aqueous layers, 26 starting with helix orientations similar to those in Figure 13(d). Although the fivefold symmetry of the pentamer was lost as the simulations proceeded, the helix orientations were generally preserved, again supporting the stability of such pentamer structures.…”

“…The goal was simply to generate well-packed oligomer models with the full range of possible s and q angles for comparison with experimental data, not to predict the structures or other properties of Vpu TM oligomers by molecular dynamics simulations in a realistic bilayer environment, as has been done previously (without direct experimental constraints) by other groups. 10,26,[30][31][32] Our approach to modeling and data analysis is similar to the approach used by Kukol and Arkin to interpret Fourier-transform infrared (FTIR) measurements on Vpu TM oligomers. 16 In our modeling procedure, oligomers with a right-handed twist about the symmetry axis have positive s, whereas those with left-handed twist have negative s. With q ¼ 0 , C a sites of I8, I15, and W22 are in the central pore of the oligomer, whereas C a sites of V13, V20, and I27 are on the outside, nearly diametrically opposite to the symmetry axis.…”

“…17 Computational modeling of oligomers of Vpu TM segments has been carried out by several groups, resulting in detailed models for tetramers, pentamers, and hexamers. 10,[24][25][26][27][28][29] Predictions of channel conductance based on these models favor a pentamer or larger oligomer as the predominant channel. 10,25 Computational studies include investigations of interactions of channel-blocking compounds with Vpu ion channels, 30 effects of site-specific mutations on secondary structure and supramolecular structure, 31 and channel selectivity.…”

Application of solid-state NMR restraint potentials in membrane protein modeling

“…The ion channel is formed by the homo-oligomers of four to seven helices. Computational studies have suggested that the most probable oligomeric state is a pentamer [46,47]. However, a recent study suggested that there might be more than one possible oligomeric state [9], and the exact state is yet to be determined.…”