Cholinesterases -acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, -attract the attention of the scientific community due to their importance for human health. Some features also make them interesting for fundamental enzymology. For instance, AChE is sometimes considered to be the pinnacle of enzyme evolution with catalytic rates approaching the diffusion limit. The degradation of acetylcholine to acetic acid and choline by this enzyme is the primary mechanism for controlling the intensity of neuromuscular impulse transmission. Loss of such regulation leads to catastrophic consequences, up to lethal, which explains the choice of hAChE (human AChE) as a target for irreversible covalent inhibition by organophosphate (OP) chemical warfare agents. It is still debated what is the main function of hBChE. This enzyme was reported to be involved in lipid metabolism including the ability to hydrolyze the hunger hormone ghrelin. Reversible non-covalent inhibition of hBChE by small molecules is thought to be a path to treat Alzheimer's disease, each year witnessing hundreds of papers with suggested drug candidates. The broad binding site of hBChE, while not making it easier to pin down the "main" physiological substrate, allows for repurposing it for desired molecules by design. This way, a family of cocaine hydrolases emerged. High similarity between two enzymes allows for the use of hBChE as a suicide agent protecting against OPs. G117H variant, its derivatives and some other variants even showed the OPase activity by slowly reactivating after covalent inhibition. The mechanism of this activity remains a matter of debate, which is at least partially powered by the lack of consensus on the number and location of hydrogen atoms on titratable residues within and around the active site. Cholinesterases are serine triad hydrolases, with the triad composed by Ser, His and Glu residues. The triad is supported by an extensive network of hydrogen bonds reaching well beyond the first interaction shell of these three residues (Figure ). We will refer to this set of hydrogen-bonded residues as an extended active site. Within this region, hAChE and hBChE feature two additional glutamate residues in close vicinity to the catalytic one. On numerous occasions it was pointed out that the simultaneous existence of all three glutamates in anionic form is highly unlikely. Nevertheless, molecular modeling and computational drug design efforts sometimes continue to model a trianionic extended active site despite introducing severe artifacts. In static docking studies or single-point quantum-mechanical/molecular-mechanical (QM/MM) calculations these artifacts are represented by an incorrect electrostatic field in the relevant region. In dynamics, electrostatic repulsion and unsaturated h-bonding networks manifest in distorted conformational ensembles. Experimental studies suggested that cholinesterases exhibit variations in flexibility with potential "breathing" motions and loop rearrangements affected by binding ligands and covalent inhibition. Zooming on this behavior with classical molecular dynamics (MD) is intriguing, but requires long-scale simulations that would be instantly invalidated by incorrect composition of the (extended) active site.