Understanding Ligand Binding to G-Protein Coupled Receptors Using Multiscale Simulations

Abstract

Human G-protein coupled receptors (GPCRs) convey a wide variety of extracellular signals inside the cell and they are one of the main targets for pharmaceutical intervention. Rational drug design requires structural information on these receptors; however, the number of experimental structures is scarce. This gap can be filled by computational models, based on homology modeling and docking techniques. Nonetheless, the low sequence identity across GPCRs and the chemical diversity of their ligands may limit the quality of these models and hence refinement using molecular dynamics simulations is recommended. This is the case for olfactory and bitter taste receptors, which constitute the first and third largest GPCR groups and show sequence identities with the available GPCR templates below 20%. We have developed a molecular dynamics approach, based on the combination of molecular mechanics and coarse grained (MM/CG), tailored to study ligand binding in GPCRs. This approach has been applied so far to bitter taste receptor complexes, showing significant predictive power. The protein/ligand interactions observed in the simulations were consistent with extensive mutagenesis and functional data. Moreover, the simulations predicted several binding residues not previously tested, which were subsequently verified by carrying out additional experiments. Comparison of the simulations of two bitter taste receptors with different ligand selectivity also provided some insights into the binding determinants of bitter taste receptors. Although the MM/CG approach has been applied so far to a limited number of GPCR/ligand complexes, the excellent agreement of the computational models with the mutagenesis and functional data supports the applicability of this method to other GPCRs for which experimental structures are missing. This is particularly important for the challenging case of GPCRs with low sequence identity with available templates, for which molecular docking shows limited predictive power.

Toward the Identification of Extra-Oral TAS2R Agonists as Drug Agents for Muscle Relaxation Therapies via Bioinformatics-Aided Screening of Bitter Compounds in Traditional Chinese Medicine

“…In humans, TAS2Rs are a family of 25 type A G protein coupled receptors (GPCRs) (versus 35 TAS2Rs in rats and mice) according to their structure and binding site location (Di Pizio et al, 2016, 2019; Alfonso-Prieto et al, 2019). Although TAS2Rs have been found in many species, in each species their genes are not highly conserved in terms of sequence.…”

Bitter taste receptor T2R14 detects quorum sensing molecules from cariogenic Streptococcus mutans and mediates innate immune responses in gingival epithelial cells

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Ceratothoa oestroides Infection in European Sea Bass: Revealing a Long Misunderstood Relationship

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