title: Penicillin's catalytic mechanism revealed by inelastic neutrons and quantum chemical theory.
abstract: Penicillin, travels through bodily fluids, targeting and acylatively inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria. Somehow, it avoids metabolic degradation remaining inactive en route. To resolve this ability to switch from a non-active, to a highly reactive form, we investigated the dynamic structure-activity relationship of penicillin by inelastic neutron spectroscopy, reaction kinetics, NMR and multi-scale theoretical modelling (QM/MM and post-HF ab initio). Results show that by a self-activating physiological pH-dependent two-step proton-mediated process, penicillin changes geometry to activate its irreversibly reactive acylation, facilitated by systemic intramolecular energy management and cooperative vibrations. This dynamic mechanism is confirmed by the first ever reported characterisation of an antibiotic by neutrons, achieved on the TOSCA instrument (ISIS facility, RAL, UK).
authors.affiliation: Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada. zoltanmucsi@gmail.com.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Mucsi
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, London, E1 4NS, UK. g.chass@qmul.ac.uk.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Chass
authors.affiliation: Department of Chemical Informatics University of Szeged, Szeged, H-6725, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Ábrányi-Balogh
authors.affiliation: Department of Chemical Informatics University of Szeged, Szeged, H-6725, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Jójárt
authors.affiliation: College of Chemistry, Beijing Normal University, Beijing, 100875, China.
authors.forename: De-Cai
authors.initials: DC
authors.lastname: Fang
authors.affiliation: ISIS Facility, STFC Rutherford Appleton Laboratory, Chilton, Didcot Oxon OX11 0QX, UK.
authors.forename: Annibal J
authors.initials: AJ
authors.lastname: Ramirez-Cuesta
authors.affiliation: Department of Chemical Informatics University of Szeged, Szeged, H-6725, Hungary.
authors.forename: Béla
authors.initials: B
authors.lastname: Viskolcz
authors.affiliation: Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada. zoltanmucsi@gmail.com.
authors.forename: Imre G
authors.initials: IG
authors.lastname: Csizmadia
mesh_terms: D000215:Acylation; D002384:Catalysis; D004583:Electrons; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009502:Neutrons; D010406:Penicillins / Q000737:chemistry*; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D010406:Penicillins