Abstract
This research uncovers the hidden conformational landscapes of proteins. By exhaustively sampling the structural states of the Kv1.2 potassium-channel’s voltage-sensing domain, we revealed a diverse ensemble of metastable conformations that drive its functional transitions. The results chart previously unobserved rare states and outline the sequence of conformational changes leading to channel activation. These findings reshape our understanding of how voltage-gated ion channels convert electrical signals into mechanical motion, highlighting the central role of conformational diversity in biological function. Beyond Kv1.2, the work demonstrates the transformative impact of comprehensive conformational sampling for decoding the dynamic behaviour of macromolecules.