Calculation of Protein Dielectric Constants using Molecular Dynamics Simulation

蛋白质是高度复杂的分子，在溶液中由大量相对较弱的相互作用结合在一起。这些相互作用对维持蛋白质的折叠结构至关重要。组成蛋白质的一些氨基酸是带电的，这种带电可以随pH变化而变化。因此，蛋白质对环境pH值的变化极为敏感。例如，在高度酸性的溶液中，蛋白质中的许多负电荷可能被中和。蛋白质内部静电相互作用的这种变化会显著影响生物分子的结构和功能。许多酶只在相对较窄的pH范围内具有催化作用，因为活性部位的化学和电荷分布需要高度特定。这种过程在理论上是非常难以理解的，因为在这些高度复杂的系统中存在大量的相互作用电荷。这个项目的目的是改进目前使用计算机模拟计算蛋白质对pH变化的响应的方法。插入蛋白质中的电荷会导致相邻带电基团的局部重排，从而使有利的静电相互作用最大化。这被称为蛋白质介电响应。这个项目将使用人工电荷探测器来测量蛋白质不同区域的介电响应，特别是将研究蛋白质内部和蛋白质/水界面之间的差异。由于水具有异常高的介电响应，预计生物分子表面对电荷插入的响应能力比内部更高。这些效应很重要，因为介电响应和蛋白质的pH依赖行为之间存在联系，这一点仍然知之甚少。这项研究将发展当前的理论，从介电响应的最基本物理定义出发，全面描述其在与pH相关的结构和功能中的作用。

Proteins are highly complex molecules held together by a large number of relatively weak interactions in solution. These interactions are critical in maintaining the folded structure of proteins. Some of the amino acids that make up the protein are charged and this charge can vary in a pH dependent way. Therefore, proteins are extremely sensitive to changes in the pH of their environment. In a highly acidic solution for instance, many of the negative charges within the protein may be neutralised. This change in the electrostatic interactions within the protein can significantly affect the structure and function of the biomolecule. Many enzymes are only catalytic over a relatively narrow range of pH as the chemistry and charge distribution of the active site needs to be highly specific. Such processes are extremely difficult to understand theoretically as there are a large number of interacting charges in these highly complex systems. The aim of this project is to improve current methods for calculating the response of proteins to changes in pH using computer simulation. A charge inserted into a protein results in a local rearrangement of neighbouring charged groups to maximise favourable electrostatic interactions. This is known as the protein dielectric response. This project will use an artificial charge probe to measure the dielectric response in various regions of the protein, and in particular will investigate the differences between the interior of proteins and the protein/water interface. The surface of the biomolecule is expected to have a higher ability to respond to charge insertion than the interior as water has an anomalously high dielectric response. These effects are important because there is a connection between the dielectric response and the pH dependent behaviour of the protein which remains poorly understood. This study will develop current theories by starting from the most basic physical definition of the dielectric response and building towards a full description of its role in pH dependent structure and function.