A Minimalist Model for Navigating Conformational Landscape Uncovers the Activation Mechanism of β2‑Adrenergic Receptor

Abstract

A mechanistic understanding of GPCR activation is essential to designing modulators for its function. The lower energy of the inactive state under basal conditions, as well as the transient nature of intermediates have impeded the characterization of GPCR’s activation mechanisms at full-atomic scale. In this study, we generate in silico thousands of full-atomic, continuous pathways, visualizing the complete activation mechanism of a broadly studied GPCR, the β2 adrenergic receptor. To this aim, we adopted a minimalist model that prioritizes the intrinsic dynamics of the receptor, combined with weighted ensemble-enhanced molecular dynamics (WEMD) simulations. Clustering analysis of the generated trajectories reveals distinct classes of activation, including an off-pathway transition, and conformational switches that enable activation. Simulations of two mutants, D1303.49A and E2686.30A, show their high propensity to get activated, consistent with experimental observations. Overall, WEMD emerges as a promising method for navigating GPCR’s conformational landscape and predicting the effects of mutations, well beyond the reach of conventional simulations.