title: The role of the peripheral anionic site and cation-pi interactions in the ligand penetration of the human AChE gorge.
abstract: We study the ligand (tetramethylammonium) recognition by the peripheral anionic site and its penetration of the human AChE gorge by using atomistic molecular dynamics simulations and our recently developed metadynamics method. The role of both the peripheral anionic site and the formation of cation-pi interactions in the ligand entrance are clearly shown. In particular, a simulation with the W286A mutant shows the fundamental role of this residue in anchoring the ligand at the peripheral anionic site of the enzyme and in positioning it prior to the gorge entrance. Once the ligand is properly oriented, the formation of specific and synchronized cation-pi interactions with W86, F295, and Y341 enables the gorge penetration. Eventually, the ligand is stabilized in a free energy basin by means of cation-pi interactions with W86.
authors.affiliation: Computational Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, USI Campus, Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Branduardi
authors.forename: Francesco Luigi
authors.initials: FL
authors.lastname: Gervasio
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000838:Anions / Q000737:chemistry; D002412:Cations / Q000737:chemistry; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*
chemical_list: D000838:Anions; D002412:Cations; D008024:Ligands; D000644:Quaternary Ammonium Compounds; D000110:Acetylcholinesterase; C027917:tetramethylammonium