Chen et al. Nat. Chem. Biol. 16, 77–86 (2020).

Allostery is mediated by a network of coupled residues that propagate small local structural changes into long-distance structural modulation. Although coupled allosteric residues can be identified from concerted motion in molecular dynamics simulations, designing allosteric control is not trivial. Chen et al. develop a framework for computational protein design that takes into account the protein conformational stability, motion, binding properties and known allosteric regulation to reprogram signaling activity. First molecular dynamics simulations are used to predict allosteric sites, followed by the use of normal-mode calculations and multi-state design for de novo design for reprogramming the long-range coupling. The researchers demonstrate on G-protein-coupled receptors (GPCRs), which involve receptor activation through highly conserved sites called microswitches. They use the method to engineer constitutive and ligand-induced G protein activation in a GPCR, the dopamine D2 receptor, for which the active-state structure is not known.