LAUSR

Macromolecules frequently associate in living cells and tissues, where specific binding interactions based on dynamic conformation regulate molecular localization and activity. Despite the rapidly expanding experimental characterization of the structural proteome, the combinatorial explosion of its interactome provides a strong motivation for the development of new tools to predict macromolecular binding modes. Molecular simulation is one such promising approach, where advances in hardware, software, and parameterization are driving increasingly accurate models of protein folding. Here, we use temperature replica-exchange simulations to study folding at a protein-protein interface and reveal the disorder-to-order transition that is necessary for binding between a G protein-coupled receptor and either a G protein or a regulatory kinase. Specifically, we recapitulate a known G protein binding mode and predict the experimentally uncharacterized binding mode of G protein coupled receptor kinase 2. The macromolecular signaling assembly that we conformationally define has important implications for kinase function and provides new insight into biased signaling from these receptors.