title: Hiding in Plain Sight: The Bimetallic Magnesium Covalent Bond in Enzyme Active Sites.
abstract: The transfer of phosphate groups is an essential function of many intracellular biological enzymes. The transfer is in many cases facilitated by a protein scaffold involving two closely spaced magnesium "ions". It has long been a mystery how these "ions" can retain their closely spaced positions throughout enzymatic phosphate transfer: Coulomb's law would dictate large repulsive forces between these ions at the observed distances. Here we show, however, that the electron density can be borrowed from nearby electron-rich oxygens to populate a bonding molecular orbital that is largely localized between the magnesium "ions". The result is that the Mg-Mg core of these phosphate transfer enzymes is surprisingly similar to a metastable [Mg2]2+ion in the gas phase, an ion that has been identified experimentally and studied with high-level quantum-mechanical calculations. This similarity is confirmed by comparative computations of the electron densities of [Mg2]2+in the gas phase and the Mg-Mg core in the structures derived from QM/MM studies of high-resolution X-ray crystal structures. That there is a level of covalent bonding between the two Mg "ions" at the core of these enzymes is a novel concept that enables an improved vision of how these enzymes function at the molecular level. The concept is broader than magnesium-other biologically relevant metals (e.g., Mn and Zn) can also form similar stabilizing covalent Me-Me bonds in both organometallic and inorganic crystals.
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , P.O. Box 12233, Research Triangle Park, North Carolina 27709-2233, United States.
authors.forename: Lalith
authors.identifier: http://orcid.org/0000-0003-0823-1631
authors.initials: L
authors.lastname: Perera
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , P.O. Box 12233, Research Triangle Park, North Carolina 27709-2233, United States.
authors.forename: William A
authors.initials: WA
authors.lastname: Beard
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , P.O. Box 12233, Research Triangle Park, North Carolina 27709-2233, United States.|Department of Chemistry, University of North Carolina at Chapel Hill , P.O. Box 3290, Chapel Hill, North Carolina 27517, United States.
authors.forename: Lee G
authors.initials: LG
authors.lastname: Pedersen
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , P.O. Box 12233, Research Triangle Park, North Carolina 27709-2233, United States.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Wilson
mesh_terms: D055162:Biocatalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D019951:DNA Polymerase beta / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011789:Quantum Theory
chemical_list: D019951:DNA Polymerase beta; C000625660:POLB protein, human; D008274:Magnesium