Vyas_2010_Chem.Biol.Interact_187_241

Butyrylcholinesterase (BuChE) is a stoichiometric bioscavenger against organophosphorus (OP) nerve agent poisoning, and efforts to make BuChE variants that are catalytically active against a wide spectrum of nerve agents have been ongoing for the last decade. In order to understand the structural consequences for BuChE, we carried out extensive molecular dynamics (MD) simulations on wild-type BuChE (PDB ID: 1P0I) and several known and new variants of this enzyme, but without the presence of any ligand in the active site. The MD simulations on WT-BuChE identified two labile orientations for the catalytic serine, and also showed the likelihood of a backdoor. Upon changes at the G116 position, severe alterations around the active site region were identified. Simulations on both G117H and G117N variants showed the existence of a bound water molecule that is in close proximity to S198. Modeling of the E197Q mutant suggested that Q197 can be in two distinct orientations, one similar to the E202Q-AChE crystal structure and another in proximity to G439 and E441. The double mutant, G117H/E197Q, was found to have structural characteristics of both G117H and E197Q. In light of the computational results, previous experimental observations are discussed.