Ligand-induced modulation of the free-energy landscape of G protein-coupled receptors explored by adaptive biasing techniques.

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 ac

SUBMITTER: Provasi D 

PROVIDER: S-EPMC3192824 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature