Calculation of Protein Dielectric Constants using Molecular Dynamics Simulation

蛋白质是高度复杂的分子，在溶液中通过大量相对弱的相互作用结合在一起。这些相互作用对于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，这种带电可以以pH值依赖的方式变化。因此，蛋白质对环境pH值的变化极为敏感。例如，在高酸性溶液中，蛋白质中的许多负电荷可能会被中和。蛋白质内部静电相互作用的这种变化可以显著影响生物分子的结构和功能。许多酶只在一个相对狭窄的pH范围内起催化作用，因为活性位点的化学和电荷分布需要高度特异性。这种过程在理论上很难理解，因为在这些高度复杂的系统中存在大量相互作用的电荷。该项目的目的是利用计算机模拟来改进目前计算蛋白质对pH变化的反应的方法。插入到蛋白质中的电荷会导致邻近带电基团的局部重排，从而使有利的静电相互作用最大化。这就是所谓的蛋白质介电反应。本项目将使用人工电荷探针来测量蛋白质各区域的介电响应，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，生物分子的表面预计比内部具有更高的电荷插入响应能力。这些影响是重要的，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。本研究将从电介质响应最基本的物理定义出发，发展当前的理论，并朝着全面描述其在pH依赖结构和功能中的作用的方向发展。

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.