Ligand-Induced modulation of the Free-Energy landscape of G protein-coupled receptors explored by adaptive biasing techniques

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Abstract

Extensive experimental information supports the formation of ligand-specific conformations of G protein-coupled receptors (GPCRs) as a possible molecular basis for their functional selectivity for signaling pathways. Taking advantage of the recently published inactive and active crystal structures of GPCRs, we have implemented an all-atom computational strategy that combines different adaptive biasing techniques to identify ligand-specific conformations along pre-determined activation pathways. Using the prototypic GPCR β2-adrenergic receptor as a suitable test case for validation, we show that ligands with different efficacies (either inverse agonists, neutral antagonists, or agonists) modulate the free-energy landscape of the receptor by shifting the conformational equilibrium towards active or inactive conformations depending on their elicited physiological response. Notably, we provide for the first time a quantitative description of the thermodynamics of the receptor in an explicit atomistic environment, which accounts for the receptor basal activity and the stabilization of different active-like states by differently potent agonists. Structural inspection of these metastable states reveals unique conformations of the receptor that may have been difficult to retrieve experimentally.

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Provasi, D., Artacho, M. C., Negri, A., Mobarec, J. C., & Filizola, M. (2011). Ligand-Induced modulation of the Free-Energy landscape of G protein-coupled receptors explored by adaptive biasing techniques. PLoS Computational Biology, 7(10). https://doi.org/10.1371/journal.pcbi.1002193

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