Structure Prediction of G-Protein Coupled Receptors

摘要: G-protein coupled receptors (GPCRs) form a large family of proteins and are very important drug targets. They membrane proteins, which makes computational prediction their structure challenging. Homology modeling is further complicated by low sequence similarly the GPCR superfamily. In this dissertation, we analyze conserved inter-helical contacts recently solved crystal structures, develop unified sequence-structural alignment We use method to align 817 human GPCRs, 399 nonolfactory. This can be used generate high quality homology models for GPCRs. To refine provided developed Trihelix sampling method. multi-scale approach simplify problem treating transmembrane helices as rigid bodies. contrast Monte Carlo methods, does complete local using discretized coordinates helices. validate on existing structures apply it predict lactate receptor, HCAR1. For also build extracellular loops taking into account constraints from three disulfide bonds. Docking 3,5-dihydroxybenzoic acid shows likely involvement Arg residues different in binding single ligand molecule. Protein relies accurate force fields. next present an effort improve charge assignment atomic models. particular, introduce formalism polarizable equilibration scheme (PQEQ) describe its implementation molecular simulation package Lammps. PQEQ allows fast fly even reactive