title: The Nature of Activated Non-classical Hydrogen Bonds: A Case Study on Acetylcholinesterase-Ligand Complexes.
abstract: Molecular recognition events in biological systems are driven by non-covalent interactions between interacting species. Here, we have studied hydrogen bonds of the CH⋅⋅⋅Y type involving electron-deficient CH donors using dispersion-corrected density functional theory (DFT) calculations applied to acetylcholinesterase-ligand complexes. The strengths of CH⋅⋅⋅Y interactions activated by a proximal cation were considerably strong; comparable to or greater than those of classical hydrogen bonds. Significant differences in the energetic components compared to classical hydrogen bonds and non-activated CH⋅⋅⋅Y interactions were observed. Comparison between DFT and molecular mechanics calculations showed that common force fields could not reproduce the interaction energy values of the studied hydrogen bonds. The presented results highlight the importance of considering CH⋅⋅⋅Y interactions when analysing protein-ligand complexes, call for a review of current force fields, and opens up possibilities for the development of improved design tools for drug discovery.
authors.affiliation: Department of Chemistry, Umeå University, 901 87, Umeå, Sweden.
authors.forename: Lotta
authors.initials: L
authors.lastname: Berg
authors.affiliation: International Institute of Information Technology, Bangalore, Karnataka, India.
authors.forename: Brijesh Kumar
authors.initials: BK
authors.lastname: Mishra
authors.affiliation: Department of Chemistry, Umeå University, 901 87, Umeå, Sweden.
authors.forename: C David
authors.initials: CD
authors.lastname: Andersson
authors.affiliation: CBRN Defense and Security, Swedish Defense Research Agency, 906 21, Umeå, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ekström
authors.affiliation: Department of Chemistry, Umeå University, 901 87, Umeå, Sweden. anna.linusson@umu.se.
authors.forename: Anna
authors.identifier: http://orcid.org/0000-0003-0063-8912
authors.initials: A
authors.lastname: Linusson
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D011789:Quantum Theory
chemical_list: D008024:Ligands; D000110:Acetylcholinesterase
keywords: acetylcholinesterase; density functional calculations; drug design; hydrogen bonds; quantum chemistry