Coarse-grained/molecular mechanics of the TAS2R38 bitter taste receptor: experimentally-validated detailed structural prediction of agonist binding

• Published in: PloS one Vol. 8; no. 5; p. e64675
• Main Authors: Marchiori, Alessandro, Capece, Luciana, Giorgetti, Alejandro, Gasparini, Paolo, Behrens, Maik, Carloni, Paolo, Meyerhof, Wolfgang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31-05-2013; Public Library of Science (PLoS)
• Subjects: Atomic structure; Binding; Bioinformatics; Biology; Biophysics; Bitter taste; Calcium; Calcium imaging; Coarsening; Computational Biology; Depth perception; Docking; G protein-coupled receptors; Genetic engineering; HEK293 Cells; Humans; Hydration; Ligands; Maternal & child health; Mechanics; Mechanics (physics); Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular modelling; Mutagenesis; Mutagenesis, Site-Directed; Neurosciences; Nutrition; Phenylthiourea; Phenylthiourea - chemistry; Propylthiouracil; Propylthiouracil - chemistry; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Proteins; Receptors; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - genetics; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Retina; Rhodopsin; Rhodopsin - chemistry; Site-directed mutagenesis; Structural Homology, Protein; Taste; Taste Buds - chemistry; Taste perception; Taste receptors; Italy; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0064675

Bitter molecules in humans are detected by ∼25 G protein-coupled receptors (GPCRs). The lack of atomic resolution structure for any of them is complicating an in depth understanding of the molecular mechanisms underlying bitter taste perception. Here, we investigate the molecular determinants of the interaction of the TAS2R38 bitter taste receptor with its agonists phenylthiocarbamide (PTC) and propylthiouracil (PROP). We use the recently developed hybrid Molecular Mechanics/Coarse Grained (MM/CG) method tailored specifically for GPCRs. The method, through an extensive exploration of the conformational space in the binding pocket, allows the identification of several residues important for agonist binding that would have been very difficult to capture from the standard bioinformatics/docking approach. Our calculations suggest that both agonists bind to Asn103, Phe197, Phe264 and Trp201, whilst they do not interact with the so-called extra cellular loop 2, involved in cis-retinal binding in the GPCR rhodopsin. These predictions are consistent with data sets based on more than 20 site-directed mutagenesis and functional calcium imaging experiments of TAS2R38. The method could be readily used for other GPCRs for which experimental information is currently lacking.