Abstract
At the joint between the membrane and hydrophilic arms of the enzyme, the structure of the respiratory complex I reveals a tunnel-like Q-chamber for ubiquinone binding and reduction. The narrow entrance of the quinone chamber located in ND1 subunit forms a bottleneck (eye of a needle) which in all resolved structures was shown to be too small for a bulky quinone to pass through, and it was suggested that a conformational change is required to open the channel. The closed bottleneck appears to be a well-established feature of all structures reported so-far, both for the so-called open and closed states of the enzyme, with no indication of a stable open state of the bottleneck. We propose a squeeze-in mechanism of the bottleneck passage, where dynamic thermal conformational fluctuations allow quinone to get in and out. Here, using molecular dynamics simulations of the bacterial enzyme, we have identified collective conformational changes that open the quinone chamber bottleneck. The model predicts a significant reduction—due to a need for a rare opening of the bottleneck—of the effective bi-molecular rate constant, in line with the available kinetic data. We discuss possible reasons for such a tight control of the quinone passage into the binding chamber and mechanistic consequences for the quinone two-electron reduction.Graphic abstract
Highlights
NADH:ubiquinone oxidoreductase, or respiratory complex I, is a key proton-pumping enzyme of the energy-generating machinery in the cell [1, 2]
The Principal Component Analysis of an Molecular Dynamics (MD) trajectory results in several collective modes Q, which are graded and ordered by the magnitute of their elasticity-strength constant k and frequency ; several such modes are listed in Table S1–S4 in SI
And previously [28], we showed that in five published structures of complex I—bacterial T. thermophilus, yeast Y. lipolytica, and three mammal, mice, ovine, and human, the bottleneck at the entrance of the quinone chamber is too narrow for a quinol or quinone to pass through it
Summary
NADH:ubiquinone oxidoreductase, or respiratory complex I, is a key proton-pumping enzyme of the energy-generating machinery in the cell [1, 2]. Complex I is an L-shaped structure with a hydrophilic domain where electron transport takes place and a membrane domain that performs proton translocation [4, 14]. The transfer of two electrons to quinone [16] is a key exergonic step, which is believed to drive local conformational changes [2, 11, 17] that transmit to the membrane domain of the complex and help to drive the proton pumping [18, 19]. The new structures have opened a new intriguing question about the mechanism of quinone binding to the enzyme, which is addressed in this paper
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