English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

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.

Molecular Dynamics Simulation of Cocaine Binding with Human Butyrylcholinesterase and Its Mutants