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

生物分子的许多重要活动都涉及原子间化学键的断裂和形成，或电子从一个分子转移到另一个分子。这些过程本质上是量子力学的，如果我们要理解它们如何以及为什么发生，我们必须使用量子力学（QM）。然而，对于比氢更大的系统，精确地求解量子力学方程是不可能的，因此，各种计算技术已经发展出来，可以计算出非常精确的方程答案，这些方程可以系统地改进。其中最成功的密度泛函理论（DFT）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，DFT的标准方法需要计算机的努力，它随着所考虑的原子数量的立方而增加。这给系统的大小设置了一个上限，可以考虑几百个原子，或者在非常大的高性能计算（HPC）中心可能有大约1000个原子。该项目将采用一种不同的DFT方法，该方法与原子数量呈线性关系，以了解称为细胞色素c氧化酶的重要酶如何通过其结构运输氢原子。当使用高性能计算中心时，这些线性缩放DFT方法可以应用于包括多达100,000或1,000,000个原子的系统，这有望在生物分子建模方面产生一场革命。细胞色素c氧化酶是一组存在于线粒体（细胞内的小结构，负责以一种叫做ATP的分子的形式产生能量，以及其他作用）中的酶之一。它是电子传递链的最后一个点，它把氧变成水，并把氢离子从膜的一边抽到另一边；然后，氢离子被用于其他地方产生ATP，为许多细胞过程提供动力。关于氢离子是如何在膜上运输的，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。我们将测试和开发用于生物化学问题的线性缩放DFT代码Conquest，并将其应用于理解细胞色素c氧化酶中中心环状结构的作用。这将为研究生物分子的结构和功能提供一种新的工具（线性标度DFT），以及了解环状结构如何参与氢转移。我们将做出具体的预测，这些预测可以通过实验来验证，并将致力于创建后续项目，这些项目建立在这个项目的结果之上，以开发氢离子和电子如何被传输并用于将氧转化为水的模型。

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.