A tiny distance makes a big difference in how the signaling proteins known as G protein-coupled receptors (GPCRs) transmit messages, according to molecular dynamics simulations (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja5055109). When biomolecules or drugs outside a cell bind membrane-spanning GPCRs, the proteins can activate any of several signaling partners inside the cell. Drugmakers want to activate the various partners at will. Wondering what drives partner selection, a team led by Peter W. Hildebrand of Berlin’s Charité University Hospital simulated the motions of the β2 adrenergic receptor, a GPCR, embedded in a lipid membrane. They included one of two peptides in the computational mix. Each peptide represented the portion of a G protein-signaling partner that contacts the GPCR. The team concludes that the GPCR’s sixth of seven transmembrane helices can orient itself in at least two stable positions, roughly 5 Å apart from one another. The bulkier of the two G protein peptides stabilizes the helix’s more open position, and the slimmer peptide stabilizes a more closed helix configuration. This corroborates what other teams observe in X-ray crystal structures and spectroscopic studies, the authors note.