Tetrameric mouse acetylcholinesterase: continuum diffusion rate calculations by solving the steady-state Smoluchowski...

Area of Science:

• Biochemistry
• Computational Biology
• Neuroscience

Background:

• Tetrameric acetylcholinesterase is crucial for neurotransmission at the neuromuscular junction and in the nervous system.
• Understanding acetylcholine diffusion to active sites is key to signal transduction.
• Crystallographic data suggests a flexible tetramer model for acetylcholinesterase.

Purpose of the Study:

• To calculate reaction rates for mouse acetylcholinesterase tetramers using different crystal structures.
• To investigate the influence of enzyme structure and ionic strength on acetylcholine diffusion and reaction rates.
• To analyze the role of electrostatic forces in acetylcholine diffusion to tetrameric enzyme active sites.

Main Methods:

• Utilized a finite element solver for the steady-state Smoluchowski equation.
• Employed two distinct mouse acetylcholinesterase tetramer crystal structures and an intermediate structure as templates.
• Calculated reaction rates for individual active sites within different tetramer conformations.

Main Results:

• Reaction rates varied among active sites in the compact tetramer structure but were similar in other structures.
• Tetramer reaction rates per active site matched monomer rates at zero salt but decreased to 67%-75% at higher ionic strength.
• Electrostatic forces significantly impact acetylcholine diffusion, playing a greater role in tetramers than monomers.

Conclusions:

• The finite element solver effectively models diffusion in complex biological geometries.
• Enzyme structure flexibility influences acetylcholinesterase activity.
• Electrostatic interactions are critical for efficient neurotransmission mediated by tetrameric acetylcholinesterase.