Department of Physics, Freie Universität Berlin, Arnimallee 14, 14159 Berlin, Germany.
Department of Physics, Freie Universität Berlin, Arnimallee 14, 14159 Berlin, Germany.
Biochim Biophys Acta Gen Subj. 2020 Aug;1864(8):129614. doi: 10.1016/j.bbagen.2020.129614. Epub 2020 Apr 17.
Determination of proton uptake pathways in Cytochrome c Oxidase is difficult due to the complexity of the system. The transition networks approach allows sampling of proton transfer pathways without predefined reaction coordinate.
Computation of the proton transfer pathways in a model of the D-channel of cytochrome c oxidase has been performed by a transition network approach that combines discrete, optimisation based and molecular dynamics based sampling.
The optimal pathway involves an opening of the so-called asparagine gate, hydration of the asparagine region, the formation of a hydrogen-bonded chain, and finally concerted proton hole transport along this chain. The optimal pathway finds the protonation of residue H26 close to the channel entrance favourable for lowering the transition energies of subsequent steps, in particular, opening of the Asn gate and formation of a hydrogen-bonded chain. Residue Y33 plays an important role in shuttling the transferred proton hole.
The optimal pathway found by the transition network approach shows the same important characteristics as pathways determined earlier by other methods. The computed barrier and reaction energies are also in good agreement with previous studies. The transition network approach provides an alternative to explore pathways in complex systems.
The correct function of the enzyme as oxidase and proton pump depends on the interplay of several redox and proton transport steps. Understanding the proton transport mechanism is therefore key to understanding the protein's function. The complex nature of long- distances proton transfer through a protein requires a non-trivial simulation strategy.
由于系统的复杂性，确定细胞色素 c 氧化酶中的质子吸收途径很困难。过渡网络方法允许在没有预定义反应坐标的情况下采样质子转移途径。
通过过渡网络方法计算细胞色素 c 氧化酶 D 通道模型中的质子转移途径，该方法结合了离散、基于优化和基于分子动力学的采样。
最佳途径涉及所谓的天冬酰胺门的打开、天冬酰胺区域的水合作用、氢键链的形成，以及最终沿着该链协同质子空穴传输。最佳途径发现靠近通道入口的残基 H26 的质子化有利于降低后续步骤的跃迁能，特别是天冬酰胺门的打开和氢键链的形成。残基 Y33 在传递质子空穴的穿梭中起着重要作用。
过渡网络方法找到的最佳途径显示出与其他方法确定的途径相同的重要特征。计算得到的势垒和反应能也与先前的研究吻合较好。过渡网络方法为探索复杂系统中的途径提供了一种替代方法。
酶作为氧化酶和质子泵的正确功能取决于几个氧化还原和质子传输步骤的相互作用。因此，了解质子传输机制是理解蛋白质功能的关键。通过蛋白质进行长距离质子转移的复杂性质需要一种非平凡的模拟策略。
