Calculation of Protein Dielectric Constants using Molecular Dynamics Simulation

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.