Conformational and Thermodynamic Landscape of GPCR Activation from Theory and Computation.

ABSTRACT: We present a hybrid computational methodology to predict multiple energetically accessible conformations for G protein-coupled receptors (GPCRs) that might play a role in binding to ligands and different signaling partners. To our knowledge, this method, termed ActiveGEnSeMBLE, enables the first quantitative energy profile for GPCR activation that is consistent with the qualitative profile deduced from experiments. ActiveGEnSeMBLE starts with a systematic coarse grid sampling of helix tilts/rotations (∼13 trillion transmembrane-domain conformations) and selects the conformational landscape based on energy. This profile identifies multiple potential active-state energy wells, with the TM3-TM6 intracellular distance as an approximate activation coordinate. These energy wells are then sampled

SUBMITTER: Dong SS 

PROVIDER: S-EPMC4919603 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature