title: The role of dimer asymmetry and protomer dynamics in enzyme catalysis.
abstract: Freeze-trapping x-ray crystallography, nuclear magnetic resonance, and computational techniques reveal the distribution of states and their interconversion rates along the reaction pathway of a bacterial homodimeric enzyme, fluoroacetate dehalogenase (FAcD). The crystal structure of apo-FAcD exhibits asymmetry around the dimer interface and cap domain, priming one protomer for substrate binding. This asymmetry is dynamically averaged through conformational exchange on a millisecond time scale. During catalysis, the protomer conformational exchange rate becomes enhanced, the empty protomer exhibits increased local disorder, and water egresses. Computational studies identify allosteric pathways between protomers. Water release and enhanced dynamics associated with catalysis compensate for entropic losses from substrate binding while facilitating sampling of the transition state. The studies provide insights into how substrate-coupled allosteric modulation of structure and dynamics facilitates catalysis in a homodimeric enzyme.
authors.affiliation: Department of Chemistry, University of Toronto, Mississauga, Ontario L5L 1C6, Canada.
authors.forename: Tae Hun
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.|Ontario Cancer Institute/Princess Margaret Cancer Centre, Campbell Family Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Pedram
authors.initials: P
authors.lastname: Mehrabi
authors.affiliation: Department of Chemistry, University of Illinois, Chicago, IL 60607, USA.|Renz Research Inc., Westmont, IL 60559, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ren
authors.affiliation: CREST, Japan Science and Technology Agency (JST), Department of Informatics, School of Science and Technology, Kwansei Gakuin University, Japan.
authors.forename: Adnan
authors.initials: A
authors.lastname: Sljoka
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Program in Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ing
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Bezginov
authors.affiliation: Department of Chemistry, University of Toronto, Mississauga, Ontario L5L 1C6, Canada.
authors.forename: Libin
authors.initials: L
authors.lastname: Ye
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Program in Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Régis
authors.initials: R
authors.lastname: Pomès
authors.affiliation: Department of Chemistry, University of Toronto, Mississauga, Ontario L5L 1C6, Canada. scott.prosser@utoronto.ca pai@hera.med.utoronto.ca.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Prosser
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada. scott.prosser@utoronto.ca pai@hera.med.utoronto.ca.|Ontario Cancer Institute/Princess Margaret Cancer Centre, Campbell Family Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
mesh_terms: D000494:Allosteric Regulation; D001426:Bacterial Proteins / Q000737:chemistry*; D055162:Biocatalysis; D018360:Crystallography, X-Ray; D019277:Entropy; D006867:Hydrolases / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D012241:Rhodopseudomonas / Q000201:enzymology*; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D014867:Water; D006867:Hydrolases; C023098:haloacetate dehalogenase