title: What can simulations tell us about GPCRs: Integrating the scales.
abstract: The functional dynamics of G protein-coupled receptors (GPCRs) encompasses multiple spatiotemporal scales, ranging from femtoseconds to seconds and Ångströms to micrometers. Computational approaches, often in close collaboration with experimental methods, have been invaluable in unraveling GPCR structure and dynamics at these various hierarchical levels. The binding of natural and synthetic ligands to the wild-type and naturally occurring variant receptors have been analyzed by several computational methods. The activation of receptors from the inactive to the active state has been investigated by atomistic simulations and ongoing work on several receptors will help uncover general and receptor-specific mechanisms. The interaction of GPCRs with complex membranes that contain phospholipids and cholesterol have been probed by coarse-grain methods and shown to directly influence receptor association. In this chapter, we discuss computational approaches that have been successful in analyzing each scale of GPCR dynamics. An overview of these approaches will allow a more judicious choice of the appropriate method. We hope that an appreciation of the power of current computational approaches will encourage more critical collaborations. A comprehensive integration of the different approaches over the entire spatiotemporal scales promises to unravel new facets of GPCR function.
authors.affiliation: CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Durba
authors.initials: D
authors.lastname: Sengupta
authors.affiliation: Savitribai Phule Pune University, Pune, India.
authors.forename: Manali
authors.initials: M
authors.lastname: Joshi
authors.affiliation: Division of Biology, IISER Pune, Pune, India.
authors.forename: Chaitanya A
authors.initials: CA
authors.lastname: Athale
authors.affiliation: CSIR-Center of Cellular and Molecular Biology, Hyderabad, India.
authors.forename: Amitabha
authors.initials: A
authors.lastname: Chattopadhyay
mesh_terms: D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072417:Protein Domains; D055503:Protein Multimerization; D011789:Quantum Theory; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000502:physiology; D015398:Signal Transduction
chemical_list: D043562:Receptors, G-Protein-Coupled
keywords: Coarse-grain; Docking; GPCR dimerization; Lipid–protein interactions; Simulations