Uncovering GPCR and G Protein Function by Protein Structure Network Analysis

Protein structure network (PSN) analysis is one of the graph theory-based approaches currently used for investigating structural communication in biomolecular systems. Information on the system's dynamics can be provided by atomistic molecular dynamics (MD) simulations or coarse grained elastic network models paired with normal mode analysis (ENM-NMA). This chapter reports on selected applications of PSN analysis to uncover the structural communication in G protein coupled receptors (GPCRs) and G proteins. Strategies to highlight changes in structural communication caused by mutations, ligand and protein binding are described. Conserved amino acids, sites of misfolding mutations, or ligands acting as functional switches tend to behave as hubs in the native structure networks. Densely linked regions in the protein structure graphs could be identified as playing central roles in protein stability and function. Changes in the communication pathway fingerprints depending on the bound ligand or following amino acid mutation could be highlighted as well. A bridge between misfolding and misrouting could be established in rhodopsin mutants linked to inherited blindness. The analysis of native network perturbations by misfolding mutations served to infer key structural elements of protein responsiveness to small chaperones with implications for drug discovery.