Journal
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
Volume 15, Issue 12, Pages 6992-7003Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jctc.9b00847
Keywords
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Funding
- MOST [106-14]
- Academia Sinica, Taiwan
- European Regional Development Fund within the Operational Programme Science and Education for Smart Growth 2014-2020 under the Project CoE National center of mechatronics and clean technologies [BG05M2OP001-1.001-0008-C01]
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Di/triphosphates perform a multitude of essential tasks, being important components of many vital organic cofactors such as adenosine/guanosine di/triphosphate (ADP/GDP, ATP/GTP), flavin adenine dinucleotide, and nicotinamide adenine dinucleotide and its phosphate derivative. They are generally bound to cations inside cells, in particular Mg2+ in the case of ATP/GTP. Yet how their metal-binding modes depend on the number, charge, and solvent exposure of the polyphosphate group and how Mg(2+)and Ca2+ dications that coexist in cellular fluids compete for di/triphosphates in biological systems remain elusive. Using density functional theory calculations combined with a polarizable continuum model, we have determined the relative free energies and stabilities of the different binding modes of di- and triphosphate groups to Mg2+ and Ca2+. We show that the thermodynamic outcome of the competition between Mg2+ and Ca2+ for cellular di/triphosphates depends mainly on the oligomericity/charge and metal-binding mode of the phosphate ligand as well as the solvent exposure of the binding site. Increasing the charge and thus denticity of the phosphate ligand from bi- to tridentate in a buried binding pocket enhances the affinity of the host system for the stronger charge acceptor, Mg2+. The cellular di/triphosphatess intrinsic properties and the protein matrix allowing them to bind a dication bi/tridentately, along with the higher cytosolic concentration of Mg2+ compared to Ca2+, enables Mg2+ to outcompete Ca2+ in binding to these highly charged anions. This suggests an explanation for why nature has chosen Mg2+ but not Ca2+ to perform most of the essential tasks associated with biological triphosphates.
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