The calculations suggest that in unliganded I19G the energetically dominant lid state is disordered and occludes the ligand binding site (label C8, Figure ). A partially open, partially helical motif is energetically feasible (label C9, Figure ). Upon docking in AM-7209, conformational preferences shift towards adoption of this partially open and helical state (label C11, Figure ). Lid conformations that wrap over the ligand become energetically disfavoured (label C12, Figure ).