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−1 for 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 bind values to evaluate binding free energies, showing a favorable ΔG bind of −36.432 kJ mol−1 for ATX-a and a slightly lower value of −30.12 kJ mol−1 for 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.