Integrative biophysical illumination of the 3D GPCRome dynamics

Insights into the dynamics of G-protein-coupled receptors (GPCRs) remain limited. Here we present an integrative strategy that bridges computational and experimental biophysical methods for probing protein dynamics. To illustrate its potential, we developed GPCRmd-NMR, a platform that synergistically combines molecular dynamics (MD) simulations with high-resolution nuclear magnetic resonance (NMR) spectroscopy across the three-dimensional GPCRome. The resulting dataset enables structure-resolved analysis by applying the strategy across multiple GPCRs. We provide access to underexplored functional GPCR dynamics, receptor states and sites, including microswitches, hidden ligand entrance gateways and intrinsically disordered regions. Our integrated framework offers a solution to challenges faced by both experimental and computational researchers including the MD-NMR timescale gap.