期刊
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
卷 17, 期 4, 页码 2444-2456出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jctc.0c01007
关键词
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资金
- Ministry of Science Technology [MOST-107-2113-M-001-018]
- Academia Sinica, Taiwan [AS-IA-107-L03]
- 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]
The study reveals that monophosphate-containing ligands prefer monodentate coordination with Mg2+ rather than Ca2+, while larger Ca2+ prefers bidentate binding. In a low-dielectric environment, negatively charged monophosphate-containing ligands favor Mg2+ binding. By promoting Mg2+ over Ca2+ binding, signaling monophosphates do not interfere with cellular Ca2+ signaling processes.
Monophosphate, an essential component of nucleic acids, as well as cell membranes and signaling molecules, is often bound to metal cations. Despite the biological importance of monophosphate-containing cell-signaling or lipid molecules, their propensity to bind the two most abundant cellular dications, Mg2+ and Ca2+, in a particular mode (inner/outer shell, mono/bidentate) is not well understood. Whether they prefer binding to Mg2+ than to Ca2+ and if they can outcompete the carboxylates of excitatory Asp/Glu and inhibitory gamma-aminobutyric acid (GABA) neurotransmitters in binding to Mg2+/Ca2+ remain unclear. To address these questions, we modeled cyclic adenosine/guanosine monophosphate (cAMP/cGMP), nucleoside 2',3'-cyclic phosphate, phosphatidylinositol (PI), phosphatidylserine (PS), and phosphatidylethanolamine (PEA) and determined their most stable metal-binding modes, including those of Asp/Glu and GABA, as well as their selectivity for Mg2+/Ca2+ using density functional theory combined with the polarizable continuum model. The results obtained, which are consistent with the available experimental findings, reveal that the structurally and functionally diverse monophosphate-containing ligands studied prefer monodentate coordination of Mg2+ because of the greater strain encountered upon bidentate coordination, whereas the larger Ca2+ imposes less strain upon bidentate binding and has reduced/no preference for monodentate coordination. We further show that in a low-dielectric environment, negatively charged monophosphate-containing ligands favor the better charge-accepting dication, that is, Mg2+ rather than Ca2+. By promoting Mg2+ over Ca2+ binding, signaling monophosphates (cAMP/cGMP) do not entrap cellular Ca2+ and interfere with signal transduction processes employing Ca2+ as a second messenger. In regions with high glutamate cytoplasmic concentration, glutamate may sequester Mg2+ bound to isolated five-/six-membered ring phosphates, PI, or neutral PEA, but not anionic phospholipids constituting the inner leaflet of the cell membrane.
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