Fig. 1. Conformational domains targeted by different docking approaches. Single-point docking utilizes a single structure of the protein target, restricting the sampling to a single point (orange dots) in the conformational landscape. Ensemble docking utilizes an ensemble of protein structures, often generated using MD simulations, taking into account thermal fluctuations within a local conformational basin in the vicinity of the starting experimental structure (blue lines). Extended-ensemble docking, the method introduced here, aims at taking into account the full functional cycle of the protein, generated, e.g., through the application of biasing techniques to transition between the major functional states of the protein (green lines).