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Butyrylcholinesterase and G116H, G116S, G117H, G117N, E197Q and G117H/E197Q mutants: a molecular dynamics study.

ABSTRACT: 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.

SUBMITTER: Vyas S

PROVIDER: S-EPMC2912153 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Butyrylcholinesterase and G116H, G116S, G117H, G117N, E197Q and G117H/E197Q mutants: a molecular dynamics study.

Vyas Shubham S Beck Jeremy M JM Xia Shijing S Zhang Jun J Hadad Christopher M CM

Chemico-biological interactions 20100504 1-3

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 ...[more]

PMID: 20399202

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Project description:Molecular dynamics (MD) simulations were carried out to study cocaine binding with wild-type human butyrylcholinesterase (BChE) and its mutants based on a recently reported X-ray crystal structure of human BChE. For each BChE-cocaine system, we simulated both the nonprereactive and prereactive complexes in water. Despite the significant difference found at the acyl binding pocket, the simulated structures confirm the fundamental structural and mechanistic insights obtained from earlier computational studies of wild-type BChE with cocaine based on a homology model, e.g. the rate-determining step for BChE-catalyzed hydrolysis of biologically active (-)-cocaine is the (-)-cocaine rotation in the active site from the nonprereactive BChE-(-)-cocaine complex to the prereactive complex. It has been demonstrated that the MD simulations on both the nonprereactive and prereactive BChE-cocaine complexes can clearly reveal whether specific mutations produce the desired BChE-(-)-cocaine binding structures in which the (-)-cocaine rotation is less hindered while the required prereactive BChE-(-)-cocaine binding is maintained. Based on the MD simulations, both A328W/Y332A and A328W/Y332G BChE's are expected to have catalytic activity for (-)-cocaine hydrolysis higher than that of wild-type BChE and the activity of A328W/Y332G BChE should be slightly higher than that of A328W/Y332A BChE due to the less-hindered (-)-cocaine rotation in the mutant BChE's. However, the less-hindered (-)-cocaine rotation is only a necessary condition for a higher activity mutant BChE. The (-)-cocaine rotation is also less hindered in A328W/Y332A/Y419S BChE, but (-)-cocaine binds with A328W/Y332A/Y419S BChE in a way that is not suitable for the catalysis. Thus, A328W/Y332A/Y419S BChE is expected to lose the catalytic activity. The computational predictions were confirmed by our experimental kinetic data, demonstrating that the MD simulation-based computational protocol used in this study is reliable in prediction of the catalytic activity of BChE mutants for (-)-cocaine hydrolysis.

Dataset Information

Butyrylcholinesterase and G116H, G116S, G117H, G117N, E197Q and G117H/E197Q mutants: a molecular dynamics study.

Publications

Butyrylcholinesterase and G116H, G116S, G117H, G117N, E197Q and G117H/E197Q mutants: a molecular dynamics study.

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