Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
Biochim Biophys Acta Bioenerg. 2021 Mar 1;1862(3):148352. doi: 10.1016/j.bbabio.2020.148352. Epub 2020 Dec 16.
The bc complex is a proton pump of the mitochondrial electron transport chain which transfers electrons from ubiquinol to cytochrome c. It operates via the modified Q cycle in which the two electrons from oxidation of ubiquinol at the Q center are bifurcated such that the first electron is passed to Cytc via an iron sulfur center and c whereas the second electron is passed across the membrane by b and b to reduce ubiquinone at the Q center. Proton pumping occurs because oxidation of ubiquinol at the Q center releases protons to the P-side and reduction of ubiquinone at the Q center takes up protons from the N-side. However, the mechanisms which prevent the thermodynamically more favorable short circuit reactions and so ensure precise bifurcation and proton pumping are not known. Here we use statistical thermodynamics to show that reaction steps that originate from high energy states cannot support high flux even when they have large rate constants. We show how the chemistry of ubiquinol oxidation and the structure of the Q site can result in free energy profiles that naturally suppress flux through the short circuit pathways while allowing high rates of bifurcation. These predictions are confirmed through in-silico simulations using a Markov state model.
bc 复合物是线粒体电子传递链的质子泵，它将电子从泛醇转移到细胞色素 c。它通过改良的 Q 循环起作用，其中泛醇在 Q 中心的氧化产生的两个电子被分叉，使得第一个电子通过铁硫中心和 c 传递到 Cytc，而第二个电子通过 b 和 b 穿过膜，在 Q 中心还原泛醌。质子泵的发生是因为 Q 中心泛醇的氧化将质子释放到 P 侧，而 Q 中心泛醌的还原从 N 侧吸收质子。然而，防止热力学上更有利的短路反应并确保精确分叉和质子泵的机制尚不清楚。在这里，我们使用统计热力学来表明，即使具有大的速率常数，也不能支持来自高能态的反应步骤具有高流量。我们展示了泛醇氧化的化学和 Q 位点的结构如何导致自由能谱，自然抑制短路途径的通量，同时允许分叉的高速率。这些预测通过使用马尔可夫状态模型的计算机模拟得到证实。
