Exploring TAS2R46 Biomechanics through Molecular Dynamics and Network Analysis

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Abstract
Understanding the intricate interplay between structural features and signal-processing events is crucial for unravelling the mechanisms of biomolecular systems. G protein-coupled receptors (GPCRs), a pervasive protein family in humans, serve a wide spectrum of vital functions. TAS2Rs, a subfamily of GPCRs, play a primary role in recognizing bitter molecules and triggering events leading to the perception of bitterness, a crucial defence mechanism against spoiled or poisonous food. Beyond taste, TAS2Rs function is associated with many diseases as they are expressed in several extra-oral tissues. Since the precise mechanism of TAS2R activation is poorly understood, this work aims to characterize the mechanisms underlying the signal transduction on the recently experimentally solved human TAS2R46 bitter taste receptor using molecular dynamics simulations coupled with network-based analysis. The results show that the allosteric activation of the receptor is associated with more correlated dynamics of the receptor and the formation of an interaction between two helices which mainly convey the signal transferring from the extracellular to the intracellular region. By elucidating the hallmarks of the allosteric network of TAS2R46 under varying conditions (ligand-bound, ligand-free, and transition states), this study has enabled the identification of the unique functional mechanisms of this receptor, thereby establishing a foundation for a more profound characterisation of this intriguing class of receptors. Highlights: The dynamics of TAS2R46 in different states were studied through molecular dynamics and network analysis. The presence of the bitter agonist increases intra-protein correlations. TM3 and TM6 helices mediate the allosteric network in Holo TAS2R46. The rotation of Y241 6.48 residue is pivotal in the allosteric network for the Holo TAS2R46.
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