Dror et al. used atomic-level simulations to show how G protein–coupled receptors trigger nucleotide exchange during GPCR signaling. They found that the G protein α subunit Ras and helical domains separate frequently and spontaneously even without a receptor, and that receptors catalyze nucleotide release by promoting a structural rearrangement of the Ras domain that weakens its nucleotide affinity. Published in Science.