Proton Pumping in Cytochrome c Oxidase

描述（由申请人提供）：本项目的目标是阐明细胞色素c氧化酶（CcO）的质子泵机制，并采用第一个动力学模拟框架来整合所有相关现象，即质子传递、电子传递和可电离氨基酸的质子化。这些现象以耦合的方式起作用。因此，质子泵送机制的完整表征将需要一个统一的方法，将它们视为这样。这将通过MS-EVB 2模型来实现，MS-EVB 2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余电离。CcO不仅是生物能量学中的一个基本好奇心，它在医学上也很重要，与癌症，神经退行性疾病和衰老等疾病有关。在正常和高能生理条件下了解其质子泵机制有助于我们认识和对抗这些疾病。此外，开发这个框架将提供一个工具，用于研究任何生物系统，其中电荷转移或质子化依赖的活动是重要的。因此，这种方法的使用可能相当广泛。

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.