Acetylcholinesterase as polyelectrolyte: interaction with multivalent cationic inhibitors

Area of Science:

• Biochemistry
• Enzymology
• Physical Chemistry

Background:

• Acetylcholinesterase (AChE) is a crucial enzyme in neurotransmission.
• Understanding enzyme-ligand interactions is vital for drug development.
• Inorganic salts can modulate enzyme activity and binding affinities.

Purpose of the Study:

• To investigate the effect of inorganic salts on cobra venom acetylcholinesterase binding with hexamethonium and gallamine.
• To apply Manning's polyelectrolyte theory to describe the electrostatic salt effect on enzyme-ligand complex dissociation.
• To determine the empirical parameter psi+1 for native and modified acetylcholinesterase.

Main Methods:

• Studied the influence of inorganic salts on the dissociation constant (KD) of enzyme-ligand complexes.
• Utilized Manning's polyelectrolyte theory and a derived equation to analyze salt effects.
• Modified acetylcholinesterase with pyromellitic dianhydride to alter its charge.

Main Results:

• Observed a negative electrostatic salt effect on the dissociation constant (KD).
• Quantitative agreement found between experimental data and Manning's theory for native AChE.
• Modification of AChE increased the psi+1 parameter, indicating increased counterion condensation.

Conclusions:

• Manning's counterion condensation model effectively describes the influence of salts on the electrostatic binding energy of AChE.
• The psi+1 parameter is a key empirical value for characterizing salt effects on different AChE forms.
• This study provides a quantitative framework for understanding salt modulation of enzyme-inhibitor interactions.