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Human butyrylcholinesterase polymorphism: Molecular modeling.

S Lushchekina1, H Delacour2, O Lockridge3

  • 1Emanuel Institute of Biochemical Physics, Moscow, Russia.

The International Journal of Risk & Safety in Medicine
|December 8, 2015
PubMed
Summary

Genetic variations in butyrylcholinesterase (BChE) can cause prolonged apnea. Molecular dynamics simulations revealed how specific BChE mutations disrupt the catalytic triad, leading to enzyme inactivation and a "silent" phenotype.

Keywords:
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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.