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

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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.