Linear Scaling Density Functional Theory for Biochemistry: Applications to Cytochrome c Oxidase

生物分子的许多重要活动涉及原子之间化学键的断裂和建立，或者电子从一个分子到另一个分子的转移。这些过程本质上是量子力学的，如果我们要了解它们是如何发生的，为什么会发生，我们必须使用量子力学(QM)。然而，对于比氢更大的体系，精确求解QM方程是不可能的，因此已经发展了各种计算技术来计算方程的极精确解，这些技术可以系统地改进。其中最成功的是密度泛函理论(DFT)，它已被广泛应用于生物化学、物理、化学、材料科学和行星科学等领域。然而，计算密度泛函的标准方法的计算量随着所考虑的原子数量的立方而增加。这给系统的大小设定了一个上限，可以认为是几百个原子，或者在非常大的高性能计算(HPC)中心上可能有1000个左右的原子。这个项目将应用一种不同的方法来研究DFT，它与原子的数量成线性关系，以了解一种名为细胞色素c氧化酶的重要酶是如何通过其结构运输氢原子的。当使用HPC中心时，这些线性标度DFT方法可以应用于包含多达100,000或1,000,000个原子的体系，这有望在生物分子建模方面产生一场革命。细胞色素c氧化酶是存在于线粒体中的一组酶之一(细胞内的小结构，负责以被称为ATP的分子的形式产生能量，以及其他作用)。它是电子转移链的最后一点，电子转移链将氧气转化为水，并将氢离子从膜的一侧泵送到另一侧；然后氢离子被用来在其他地方产生ATP，为许多细胞过程提供动力。关于氢离子是如何通过膜传输的，以及这与氧化学是如何联系在一起的，还有一些悬而未决的问题。我们将测试和开发我们的线性比例DFT程序Conquest，用于生物化学问题，我们将应用它来理解细胞色素C氧化酶中中心环状结构的作用。这将导致一个新的工具来研究生物分子的结构和功能(线性标度密度泛函)，以及对环状结构如何参与氢转移的理解。我们将做出可以通过实验检验的具体预测，并将致力于创建后续项目，以此项目的结果为基础，开发氢离子和电子如何传输和使用以将氧气转化为水的模型。

Many of the important activities of biomolecules involve the breaking and making of chemical bonds between atoms or the transfer of electrons from one molecule to another. These are processes which are inherently quantum mechanical in their nature, and if we are to understand how and why they occur we must use quantum mechanics (QM). However, solving the QM equations exactly is impossible for systems larger than hydrogen, so a variety of computational techniques have been developed which calculate extremely accurate answers to the equations which can be systematically improved. The most successful of these, density functional theory (DFT), has been applied to a wide range of fields, including biochemistry, physics, chemistry, materials science and planetary science. However, the standard approaches to DFT have a computer effort which increases with the cube of the number of atoms considered. This puts an upper limit on the size of system which can be considered of a few hundred atoms, or possibly around a thousand atoms on very large, high performance computing (HPC) centres. This project will apply a different approach to DFT, which scales linearly with the number of atoms, to understanding how an important enzyme called cytochrome c oxidase transports hydrogen atoms through its structure. These linear scaling DFT methods can be applied to systems including up to 100,000 or 1,000,000 atoms when using HPC centres, which promises to produce a revolution in modelling of biomolecules. Cytochrome c oxidase is one of a set of enzymes that reside in the mitochondria (small structures inside cells which are responsible for energy production in the form of a molecule called ATP, among other roles). It it the final point of an electron transfer chain which turns oxygen into water, and pumps hydrogen ions from one side of a membrane to another; the hydrogen ions are then used elsewhere to create ATP, which powers many cellular processes. There are outstanding questions about how the hydrogen ions are transported across the membrane, and how this links to the oxygen chemistry. We will test and develop our linear scaling DFT code, Conquest, for biochemistry problems, and we will apply it to understanding the role of a central ring-like structure within cytochrome c oxidase. This will result in a new tool for studying the structure and function of biomolecules (linear scaling DFT) as well as an understanding of how the ring-like structure is involved in hydrogen transfer. We will make specific predictions which can be tested by experiments, and will aim to create follow-on projects which build on the results of this project to develop models for how the hydrogen ions and electrons are transported and used to turn oxygen into water.