title: The role of Li+, Na+, and K+ in the ligand binding inside the human acetylcholinesterase gorge.
abstract: Alkali cations can affect the catalytic efficiency of enzymes. This is particularly true when dealing with enzymes whose substrate bears a formal positive charge. Computational and biochemical approaches have been combined to shed light on the atomic aspects of the role of Li(+), Na(+), and K(+) on human acetylcholinesterase (hAChE) ligand binding. In this respect, molecular dynamics simulations and our recently developed metadynamics method were applied to study the entrance of the three cations in the gorge of hAChE, and their effect on the dynamical motion of a ligand (tetramethylammonium) from the bulk of the solvent into the deep narrow enzyme gorge. Furthermore, in order to support the theoretical results, K(M) and k(cat) for the acetylcholine hydrolysis in the presence of the three cations were evaluated by using an approach based on the Ellman's method. The combination of computational and biochemical experiments clearly showed that Li(+), Na(+), and K(+) may influence the ligand binding at the hAChE gorge.
authors.affiliation: Computational Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, USI Campus, CH-6900 Lugano, Switzerland.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Petraglio
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Davide
authors.initials: D
authors.lastname: Branduardi
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
authors.forename: Francesco Luigi
authors.initials: FL
authors.lastname: Gervasio
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002414:Cations, Monovalent / Q000737:chemistry; D003198:Computer Simulation; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008024:Ligands; D008094:Lithium / Q000737:chemistry* / Q000378:metabolism; D011188:Potassium / Q000737:chemistry* / Q000378:metabolism; D012964:Sodium / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002414:Cations, Monovalent; D008024:Ligands; D008094:Lithium; D012964:Sodium; D000110:Acetylcholinesterase; D011188:Potassium