Research ArticleBIOPHYSICS

Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP6)

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Science Advances  16 Sep 2020:
Vol. 6, no. 38, eabc6465
DOI: 10.1126/sciadv.abc6465
  • Fig. 1 IP6 binds to the CA hexamer and pentamer.

    (A) The fullerene structure of HIV capsids contains exactly 12 pentameric defects. The geometry for the HIV-1 capsid was derived from cryo–electron tomography images of intact virions (6). Pentameric defects are colored red. (B) Two IP6 molecules bind to the R18 ring in the central pore of the CA hexamer (PDB ID: 5HGL) after 0.73 μs of AA MD simulations. The bound complex is shown in a top-down and side view. (C) A single IP6 molecule binds to the R18 ring at a pore in the CA pentamer (PDB ID: 5MCY) after 1.98 μs of AA MD simulations. The bound complex is shown in a top-down and side view. In the MD simulations for (B) and (C), IP6 molecules were initially placed in bulk solvent, ~10 Å away from the CA domains. The NTD of CA is colored in green, and the CTD of CA is colored in brown. R18 residues are shown in cyan.

  • Fig. 2 Mechanism of IP6 binding to CA pentamers.

    A series of snapshots from part of an MD trajectory show the chemical interactions involved in IP6 binding to the CA pentamer. Three CA domains are shown in a side view of the pentamer, with helix H1 of the CA domain labeled as α, β, and γ, respectively. Two additional CA domains (δ and ε) are not shown for clarity. The R18 ring and residues (K25-E29) that form a salt-bridge interaction proximal to the CTD are labeled. Time points are labeled in the upper-right corner of each panel. (A) The IP6 ligand is initially in bulk solvent. (B) Close-up view of the pore region in (A). (C) IP6 enters the pore past the β-hairpin of CA, and an arginine side chain flips away from the R18 ring. (D) The R18 side chain coordinates IP6. (E) IP6 is coordinated to multiple R18 side chains. (F) IP6 shifts toward the R18 ring. (G) IP6 reorients in the binding pocket. (H) IP6 is bound to the central arginine ring with R18 side chains contacting the negatively charged phosphates.

  • Fig. 3 Mechanism of IP6 binding to CA hexamers.

    A series of snapshots from part of an MD trajectory show the chemical interactions involved in IP6 binding to the CA hexamer. Four CA domains are shown in a side view of the hexamer, with helix H1 of the CA domain labeled as α, β, γ, and δ, respectively. Two additional CA domains (ε and ζ) are not shown for clarity. The R18 ring and residues (K25-E29) that form a salt-bridge interaction proximal to the CTD are labeled. Time points are labeled in the upper-right corner of each panel. (A) IP6 molecules are initially in bulk solvent (two are shown). (B) Close-up view of the pore region in (A). (C) An IP6 ligand enters the pore region from the CTD of CA. The K25-E29 salt-bridge interaction breaks, and K25 contacts IP6. (D) A R18 side chain flips toward the CTD to coordinate IP6. (E) IP6 binds at the CTD side of the R18 ring. (F) A second IP6 ligand enters the pore region, coordinated by an R18 side chain. (G) Multiple R18 side chains contact the second IP6 ligand. (H) Two IP6 molecules are bound to the R18 ring. Contacts between IP6 and K25 are broken, and salt-bridge interactions between K25 and E29 reform.

  • Fig. 4 Ligand density maps for IP6.

    The ligand densities are contoured at ρ = 0.05, 0.11, and 0.50 from orange to red, overlaid onto the structure of the CA pentamer, in a top-down view (A) and side view (B). Ligand densities are contoured at ρ = 0.02, 0.09, and 0.50 from light blue to dark blue, overlaid onto the structure of the CA hexamer in a top-down view (C) and side view (D). Densities contributing to interactions at sites 1, 2, and 3 are labeled in the figure, whereas densities proximal to the CA CTD (brown) form a third interaction site.

  • Fig. 5 The PMF for IP6 binding.

    The order parameter, ξ, is used to describe IP6 transport to the R18 ring. ξ is defined as the projection of the center-of-mass displacement between IP6 and R18 residues onto the pore axis and is shown schematically for the CA hexamer (A) and the CA pentamer (B). The NTD is colored in green, whereas the CTD is colored in brown. Residues R18, K25, and K29 are labeled. (C) The 1D PMF for the CA hexamer is shown in blue. The shaded light blue regions denote the error in the PMF determined by block averaging. (D) The 1D PMF for the CA pentamer is plotted in orange. The shaded light-orange regions denote the error in the PMF determined by block averaging. The pore axis is oriented such that positive values correspond to the CA NTD, whereas negative values correspond to the CA CTD.

Supplementary Materials

  • Supplementary Materials

    Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP6)

    Alvin Yu, Elizabeth M. Y. Lee, Jaehyeok Jin, Gregory A. Voth

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