A multi-institutional effort by teams from our lab at TU Darmstadt, ETH Zurich, ITMP Hamburg, AbbVie Ludwigshafen and MPI Munich revealed how conformational changes are coupled and propagated like in a domino cascade to govern the overall behaviour of macrocycles – now out in J Med Chem. A huge thanks to all team members and backing from the MC4DD and ProxiDRUGS consortia.