[19] Integrated Methods for the Construction of Three-Dimensional Models and Computational Probing of Structure-Function Relations in G Protein-Coupled Receptors

This chapter discusses the integrated methods for the construction of three-dimensional models and computational probing of structure–function relations in G protein-coupled receptors (GPCR). The rapid pace of cloning and expression of G protein-coupled receptors offers attractive opportunities to probe the structural basis of signal transduction mechanisms at the level of these cell-surface receptors. Major insights have emerged from comparisons and classifications of the amino acid sequences of GPCRs into families defined by evolutionary developments and adapted to perform selective functions. Structural data on GPCRs, based on biochemical, immunological, and biophysical approaches have validated consensus architecture of GPCRs with an extracellular N-terminus, a cytoplasmic C-terminus, and a transmembrane portion comprised of seven-transmembrane helical domains connected by loops. Developments in the molecular modeling and computational exploration of GPCR proteins indicate a tantalizing potential to alleviate some of these difficulties. These expectations are based on the increased rate of success achieved by molecular modeling and computational simulation methods in providing structural insights relevant to the functions of biological molecules.