Proton Pumping in Cytochrome c Oxidase

描述(申请人提供)：这个项目的目标是阐明细胞色素C氧化酶(CcO)的质子泵机制，并建立第一个包含所有相关现象的动力学模拟框架，即质子传输、电子传输和可电离氨基酸的质子化。这些现象以一种耦合的方式起作用。因此，对质子抽运机制的完整描述将需要一种统一的方法来对待它们。这将通过MS-EVB2模型来实现，该模型是能够模拟质子动力学的少数理论之一，扩展到包括电子转移和残基电离。CCO不仅是生物能量学中的一个基本问题，而且在医学上也很重要，因为它与癌症、神经退行性变和衰老等疾病有关。了解其在正常和高能生理条件下的质子泵机制，将有助于我们认识和抗击这些疾病。此外，开发这一框架将为研究电荷转移或质子化依赖活动非常重要的任何生物系统提供工具。因此，这种方法的使用可能是相当广泛的。

DESCRIPTION (provided by applicant): The goal of this project is to elucidate the proton pumping mechanism of cytochrome c oxidase (CcO) with the first dynamical simulation framework to incorporate all of the relevant phenomena, namely proton transport, electron transport, and the protonation of ionizable amino acids. These phenomena act in a coupled manner. Thus, the complete characterization of the proton pumping mechanism will require a unified methodology that treats them as such. This will be accomplished with the MS-EVB2 model, one of a few theories able to simulate proton dynamics, extended to incorporate electron transfer and residue ionization. CcO is not only a fundamental curiosity within bioenergetics, it is also medically important having been linked to diseases such as cancer, neurodegeneration, and aging. Understanding its proton pumping mechanism under normal and high energy physiological conditions will contribute to our knowledge of and fight against these diseases. Additionally, developing this framework will provide a tool for investigating any biological system where charge transfer or protonation-dependent activity is of importance. Thus, the use of this methodology is potentially quite broad.