Theoretical Studies of G-Protein-Coupled Receptors

The family of G-protein-coupled receptors (GPCRs) contains the largest number of drug targets in the human body, with more than a quarter of the clinically used drugs targeting them. Because of the important roles GPCRs play in the human body, the mechanisms of activation of GPCRs or ligands binding to GPCRs have captivated much research interest since the discovery of GPCRs. A number of GPCR crystal structures determined in recent years have provided us with unprecedented opportunities in investigating how GPCRs function through the conformational changes regulated by their ligands. This has motivated me to perform molecular dynamics (MD) simulations in combination with a variety of other modeling methods to study the activation of some GPCRs and their ligand selectivity. This thesis consists of six chapters. In the first chapter, a brief introduction of GPCRs and MD simulation techniques is given. Detailed MD simulation techniques, including pressure controlling methods and temperature coupling approaches, are described in chapter 2. The metadynamics simulation technique, used to enhance conformational sampling, is described in chapter 3. In chapter 4, I outline the inhomogeneous fluid theory used to calculate the thermodynamics properties of interfacial water molecules. Using the methods described in chapters 2-4, I carried out theoretical investigations on some GPCRs with the results summarized in chapter 5. In chapter 6, I provide a summary of the thesis with future work outlined in an outlook. QC 201505020