Research ArticleBIOCHEMISTRY

How cardiolipin modulates the dynamics of respiratory complex I

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Science Advances  20 Mar 2019:
Vol. 5, no. 3, eaav1850
DOI: 10.1126/sciadv.aav1850
  • Fig. 1 Structure and function of the respiratory complex I (PDB ID: 4HEA).

    Electrons are transferred from the NADH/FMN (flavin mononucleotide) site to quinone (Q) via a tunneling wire comprising eight iron-sulfur centers. The Q reduction takes place at the interface between the hydrophilic and membrane domains and couples to the pumping of four protons across the membrane. The global bending (PC1, blue arrows) and twisting motions (PC2, red arrows) are shown along two principal axes (see text). Inset: Comparison of atomistic and coarse-grained molecular simulation models of a cardiolipin molecule.

  • Fig. 2 Cardiolipin binding sites in complex I.

    (A) Top: Cardiolipin (CDL) binding sites identified by CG-MD simulations of complex I from Thermus thermophilus. Bottom: Experimentally refined CDL molecules around cryo-EM structures of complex I from Ovis aries (6) (PDB ID: 5LNK) and Mus musculus (7) (PDB ID: 6G2J). Note that TM helices 1 to 3 of subunit Nqo14 (subunit in yellow, T. thermophilus) are not present in the homologous mammalian ND2 subunits. Both enzymes are viewed from the N-side of the membrane. The supernumerary subunits are omitted for visual clarity. (B) Statistics of lipid contacts with the membrane domain of complex I obtained from CG-MD simulations. (C) Autocorrelation function of the lipid binding dynamics. The average retention time for CDL is about six times higher than that for POPE or POPC, and ca. 12 times higher than that for Nqo8-bound CDL. (D) Top: Membrane-exposed phenylalanine residues in Nqo8. Bottom: Electrostatic potential map of complex I (front view). The color scale ranges from +10 kBT/e (blue, ca. +260 mV) to −10 kBT/e (red, ca. −260 mV). (E) Putative CDL binding sites in Nqo8, obtained from atomistic simulations, highlighting interactions with Arg37, Arg41, and phenylalanine residues.

  • Fig. 3 Effect of CDL on the dynamics of complex I.

    (A) The coupled twisting-bending motion (PC3) is strongly influenced by CDL binding to complex I. The crystal structure is taken as reference conformation for the PC. (B) Structural changes in the membrane domain (view from the N-side) induced by cardiolipin binding at the Nqo13/Nqo14 interface. (C) Cardiolipin induces conformational changes at the interface between Nqo8 and the hydrophilic domain. The figure shows the distance between helix TM1 of Nqo8 and helix 1 of Nqo9.

  • Fig. 4 CDL modulates quinone and complex I dynamics.

    (A) Projection of complex I dynamics with and without CDL along the bending (PC1) and twisting (PC2) modes sorted by the quinone (Q) position along the tunnel. The quinone position is determined by the distance between the quinone headgroup and Tyr87. The quinone motion along the cavity is coupled to the complex I motion along the bending and twisting modes. (B) Quinone binding sites and channels connecting the quinone cavity with the N-side of the membrane. The upper binding sites (d ~ 0.6 to 0.8 nm from Tyr87) are shown as green and blue circles, the kink region is marked at d ~ 2.0 nm, and the lower binding sites (d ~ 3.2 to 4.0 nm) are shown as a yellow oval. Channel 1 (blue) is located near the Nqo7 loop region, and channel 2 (in red) is located at the interface between Nqo8 and Nqo9. Both channels are more stable in simulations with CDL and when quinone is bound at the upper site (d ~ 0.6 to 0.8 nm) (see also movie S2). Inset: Distance between Tyr87 and the kink region and different quinone binding sites. (C) Schematic representation of structural changes in complex I that couple to the quinone motion. (D) Probability of finding open cavities connected to the quinone binding site.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/3/eaav1850/DC1

    Fig. S1. Comparison of cardiolipin molecules bound to Nqo8 from coarse-grained and atomistic models.

    Fig. S2. The structure of the membrane domain of complex I from T. thermophilus.

    Fig. S3. Electrostatic potential surface of the bacterial and mammalian complex I.

    Fig. S4. Global motion of complex I with and without cardiolipin.

    Fig. S5. Projection of complex I dynamics with and without cardiolipin along the bending (PC1) and twisting (PC2) modes.

    Table S1. Overview of all coarse-grained MD simulations.

    Table S2. Residues within 3 Å of putative channels 1 and 2.

    Movie S1. Cardiolipin binding to complex I from a coarse-grained simulation trajectory.

    Movie S2. Cardiolipin-induced channel formation dynamics.

  • Supplementary Materials

    The PDF file includes:

    • Fig. S1. Comparison of cardiolipin molecules bound to Nqo8 from coarse-grained and atomistic models.
    • Fig. S2. The structure of the membrane domain of complex I from T. thermophilus.
    • Fig. S3. Electrostatic potential surface of the bacterial and mammalian complex I.
    • Fig. S4. Global motion of complex I with and without cardiolipin.
    • Fig. S5. Projection of complex I dynamics with and without cardiolipin along the bending (PC1) and twisting (PC2) modes.
    • Table S1. Overview of all coarse-grained MD simulations.
    • Table S2. Residues within 3 Å of putative channels 1 and 2.
    • Legends for movies S1 and S2

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    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.mov format). Cardiolipin binding to complex I from a coarse-grained simulation trajectory.
    • Movie S2 (.mov format). Cardiolipin-induced channel formation dynamics.

    Files in this Data Supplement:

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