Human butyrylcholinesterase polymorphism: Molecular modeling

Area of Science:

• Biochemistry
• Pharmacology
• Computational Biology

Background:

• Prolonged apnea after ester-containing muscle relaxants is linked to butyrylcholinesterase (BChE) deficiency.
• Genetic variations in the BCHE gene are the primary cause of BChE deficiency.
• Over 75 natural BCHE gene mutations have been identified, affecting enzyme activity.

Purpose of the Study:

• To investigate how novel BChE variants, Val204Asp and Ala34Val, cause a "silent" phenotype.
• To understand the molecular mechanisms behind prolonged neuromuscular block induced by these mutations.

Main Methods:

• Molecular dynamics (MD) simulations using NAMD 2.9 software.
• 100 ns MD runs were performed on wild-type BChE and its Val204Asp and Ala34Val mutants.
• Simulations were conducted under controlled conditions (298 K, 1 atm).

Main Results:

• The catalytic triad of BChE mutants was disrupted, preventing enzymatic activity, unlike wild-type BChE.
• Val204Asp mutation altered the hydrogen bonding network, increasing distances within the catalytic triad.
• Ala34Val mutation caused Ω-loop fluctuations, disrupting the gorge structure and catalytic triad.

Conclusions:

• MD simulations can differentiate the effects of mutations at the same BCHE gene locus.
• The study elucidates the molecular basis for the "silent" phenotype in specific BChE variants.