Acetylcholinesterase (AChE) is an enzyme essential for termination of nerve signalling by hydrolysis of the neurotransmitter acetylcholine. Non-covalent inhibitors of AChE are used for symptomatic treatment of for instance Alzheimer's disease. Organophosphorus nerve agents (OPNAs) instead bind covalently to AChE blocking its function, resulting in essentially permanent inhibition leading to paralysis and death. OPNAs pose a great threat due to their use in chemical warfare and terrorist attacks, and currently there is no broad spectrum antidote available for treatment of intoxication by all the different OPNAs available. The aim of this project is to elucidate the mechanism of therapeutic antidotes used for intoxication by OPNAs. Previous research has focused on AChE from mouse (mAChE) where the dynamics has been thoroughly investigated using MD simulations. We now aim to use this knowledge to further study AChE*OPNA complexes including antidotes, and also investigate AChE from human (hAChE). In addition to conventional MD simulations, accelerated and steered MD simulations will also be explored to accelerate conformational sampling. We hypothesize that a detailed knowledge of how the reactivation by therapeutic antidotes occur on a 3D structural- and chemical mechanistic level will provide new opportunities to discover and develop novel broad-spectrum antidotes. We have multiple 3D structures of AChE (both crystal structures and cryo-EM structures) and believe that the global dynamics of the complete monomer as well as the dimer, and also the local dynamics of the OPNA adduct and the antidote including surrounding residues, are of importance. Furthermore, the importance of conserved water molecules for ligand binding to AChE has been previously highlighted, and we aim to investigate the water population over the MD simulation time including the effect of antidote binding and OPNA inhibition. In addition we have recently used HDX-MS to determine dynamic properties of AChE which will be connected to the MD simulations including the analysis of the water network.