Abstract
Respiratory complex I performs the reduction of quinone (Q) to quinol (QH2) and pumps protons across the membrane. Structural data on complex I have provided spectacular insights into the electron and proton transfer paths, as well as into the long (~30 Å) and unique substrate binding channel. However, due to missing structural information on Q binding modes, it remains unclear how Q reduction drives long range (~20 nm) redox-coupled proton pumping in complex I. Here we applied multiscale computational approaches to study the dynamics and redox chemistry of Q and QH2. Based on tens of microseconds of atomistic molecular dynamics (MD) simulations of bacterial and mitochondrial complex I, we find that the dynamics of Q is remarkably rapid and it diffuses from the N2 binding site to another stable site near the entrance of the Q channel in microseconds. Analysis of simulation trajectories also reveal the presence of yet another Q binding site 25–30 Å from the N2 center, which is in remarkable agreement with the electron density observed in recent cryo electron microscopy structure of complex I from Yarrowia lipolytica. Quantum chemical computations on the two Q binding sites closer to the entrance of the Q tunnel reveal redox-coupled protonation reactions that may be important in driving the proton pump of complex I.
Highlights
The first enzyme in the electron transport chains of mitochondria and many bacteria is respiratory complex I, which transfers electrons released upon NADH oxidation to a quinone (Q) molecule, reduction of which to quinol (QH2) drives the proton pumping across the membrane (Supplementary Figure 1 and Figure 1) (Wikstrom et al, 2015)
We performed long time scale fully atomistic molecular dynamics (MD) simulations of bacterial and mammalian complex I structures from Thermus thermophilus [T.t., PDB id 4HEA (Baradaran et al, 2013)] and Bos taurus [B.t., PDB id 5LC5(Zhu et al, 2016)], respectively
MD simulations of both long-tailed Q and QH2 molecules reveal tight coupling between the dynamics of protein and its rapid diffusion in the Q chamber (Supplementary Videos S1, S2) in which highly conserved histidine carrying β1-β2 loop of subunit Nqo4 (H34/38 and H55/59 in T.t. and B.t., respectively), as well as the Q-cavity facing loops of Nqo6 and Nqo8 subunits rearrange as Q travels through the channel
Summary
The first enzyme in the electron transport chains of mitochondria and many bacteria is respiratory complex I, which transfers electrons released upon NADH oxidation to a quinone (Q) molecule, reduction of which to quinol (QH2) drives the proton pumping across the membrane (Supplementary Figure 1 and Figure 1) (Wikstrom et al, 2015). We modeled a Q molecule at site #4 in several different redox-protonation states, and observed water-protein based connection between the Q tunnel and the first putative proton transfer channel in the antiporterlike subunits (Haapanen and Sharma, 2017).
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