An exploration of the binding prediction of anatoxin-a and atropine to acetylcholinesterase enzyme using multi-level computer simulations

Acetylcholinesterase (AChE) is crucial for the breakdown of acetylcholine to acetate and choline, while the inhibition of AChE by anatoxin-a (ATX-a) results in severe health complications. This study explores the structural characteristics of ATX-a and its interactions with AChE, comparing to the reference molecule atropine for binding mechanisms. Molecular docking simulations reveal strong binding affinity of both ATX-a and atropine to AChE, interacting effectively with specific Amino acids in the binding site as potential inhibitors. Quantitative assessment using the MM-PBSA method demonstrates a significantly negative binding free energy of -81.659 kJ mol^-1for ATX-a, indicating robust binding, while atropine exhibits a stronger binding affinity with a free energy of -127.565 kJ mol^-1. Umbrella sampling calculates the ΔG_bindvalues to evaluate binding free energies, showing a favorable ΔG_bindof -36.432 kJ mol^-1for ATX-a and a slightly lower value of -30.12 kJ mol^-1for atropine. This study reveals the dual functionality of ATX-a, acting as both a nicotinic acetylcholine receptor agonist and an AChE Inhibitor. Remarkably, stable complexes form between ATX-a and atropine with AChE at its active site, exhibiting remarkable binding free energies. These findings provide valuable insights into the potential use of ATX-a and atropine as promising candidates for modulating AChE activity.

DFT; MM-PBSA; acetylcholinesterase; anatoxin-a; atropine; micro-second simulations; umbrella sampling.