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.
Highlights
G-protein coupled receptors (GPCRs) are one of the largest protein superfamilies, with more than 800 (4%) genes in humans (Venter et al, 2001; Fredriksson et al, 2003; Lagerstrom and Schioth, 2008; Tikhonova and Fourmy, 2010)
The first test (Leguèbe et al, 2012) showed that the molecular mechanics and coarse grained (MM/coarse grained (CG)) approach is able to preserve the receptor/ligand complex structure observed in the crystal structure, as well as to provide dynamical and hydration information similar to the AA simulations, but at a lower computational cost
The two previous tests can be considered as redocking experiments: even though the system was converted from AA into hybrid molecular mechanics (MM)/CG [test (i)] or the ligand was moved out of place [test (ii)], the binding residues were already positioned as in the correct binding pose
Summary
G-protein coupled receptors (GPCRs) are one of the largest protein superfamilies, with more than 800 (4%) genes in humans (Venter et al, 2001; Fredriksson et al, 2003; Lagerstrom and Schioth, 2008; Tikhonova and Fourmy, 2010). They detect a wide variety of extracellular signals (from photons to hormones and neurotransmitters) and trigger a myriad of intracellular transduction cascades (using different G-proteins and second messengers) (Alexander et al, 2017). Molecular dynamics (MD) simulations started from these experimental structures have provided very important insights into ligand binding and receptor activation (Miao and McCammon, 2016; Sengupta et al, 2016; Latorraca et al, 2017; Marino and Filizola, 2018; TorrensFontanals et al, 2018; Velgy et al, 2018)
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