Simulating proton transport at decorated surfaces and in cytochrome c oxidase by Q-HOP molecular dynamics simulations

在生物细胞中，完整的跨膜蛋白负责维持生物膜上的pH梯度。一个非常重要的系统是细胞色素c氧化酶(COX)，它催化细胞呼吸的最后一步，在线粒体和许多细菌的内膜中，细胞色素c到O2的四电子转移。基于COX的几种X射线结构，提出了两种可能的质子转移途径，它们似乎与催化循环的不同部分有关。然而，在COX中，质子转移到氧化还原过程的耦合在很大程度上是未知的。我们已经开发了一种有效的分子模拟方法，称为Q-HOP分子动力学(MD)，它将生物分子系统固定滴定状态的经典MD模拟与随机质子跳跃过程相结合。利用这种方法，我们首次通过无偏MD模拟表征了有机溶质在溶液中的动态质子化平衡。此外，该方法以前已经成功地应用于绿色荧光蛋白和水通道蛋白中的质子转移过程。在这里，我们建议应用一个精炼版本的QHOP MD来回答尚未解决的问题，即表面介导的质子转移以及细胞色素C氧化酶中的质子转移。

In biological cells, integral transmembrane proteins are responsible for maintaining a pH gradient across biological membranes. One very important system is cytochrome c oxidase (COX) that catalyzes the terminal step in cellular respiration, a four-electron transfer from cytochrome c to O2, in the inner membrane of mitochondria and many bacteria. Based on several X-ray structures of COX, two possible proton transfer pathways have been suggested that appear to be associated with different parts of the catalytic cycle. The coupling of proton transfers to the redox processes in COX is, however, largely unknown. We have previously developed an efficient molecular simulation method termed Q-HOP molecular dynamics (MD) that couples classical MD simulations for fixed titration states of a biomolecular system with stochastic proton hopping processes. Using this method, we were the first to characterize dynamic protonation equilibria of organic solutes in solution by unbiased MD simulations. Also, the method has been previously successfully applied to proton transfer processes in the green fluorescent protein and in aquaporin. Here, we propose to apply a refined version of QHOP MD to answer unresolved questions of surface-mediated proton transfer as well as of proton transport in cytochrome c oxidase.