Importance of Metal Hydration on the Selectivity of Mg2+ versus Ca2+ in Magnesium Ion Channels

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• 作者：Todor Dudev ; Carmay Lim
• 刊名：Journal of the American Chemical Society
• 出版年：2013
• 出版时间：November 13, 2013
• 年：2013
• 卷：135
• 期：45
• 页码：17200-17208
• 全文大小：452K
• 年卷期：v.135,no.45(November 13, 2013)
• ISSN：1520-5126

文摘

Magnesium ion channels and transporters regulate the cellular concentrations of Mg²⁺, which must be tightly controlled as imbalances have been associated with diseases such as osteoporosis, diabetes, and high blood pressure in humans. The channels and transporters allow the 鈥渘ative鈥?Mg²⁺ to be transported against a high background concentration of its major competitor, Ca²⁺. Their selectivity filters (the narrowest part of the open pore) control metal ion selectivity. As the structures of Mg²⁺ channels in an open conformation with bound Mg²⁺ have not yet been solved, the key determinants of Mg²⁺/Ca²⁺ selectivity in Mg²⁺ ion channels remain elusive. Here, using density functional theory combined with continuum dielectric methods, we evaluated how the competition between Mg²⁺ and Ca²⁺ in model selectivity filters depends on the degree of metal hydration, which correlates with the pore size/rigidity as well as the composition and solvent accessibility of the selectivity filter. The key determinant of the selectivity for Mg²⁺ over Ca²⁺ in the Mg²⁺ channel selectivity filter is a pore that is sufficiently large to accommodate hexahydrated Mg ions. In such wide pores, the hexahydrated metal ions interact indirectly with the protein ligands, hence metal desolvation and ligand鈥搇igand steric repulsion become less important than Mg²⁺鈥搘ater鈥損rotein interactions. These wide pores are Mg²⁺-selective because compared to Ca²⁺ or Na⁺ and K⁺ monocations, Mg²⁺ better polarizes the bound water molecules resulting in stronger Mg²⁺鈥搘ater鈥損rotein interactions. Although both tetrameric and pentameric filters with pores that can accommodate hexahydrated metal ions could select Mg²⁺ over Ca²⁺, a bilayered pentameric filter lined with a ring of amides and a ring of carboxylates seems to best discriminate the 鈥渘ative鈥?Mg²⁺ from its key rival, Ca²⁺. Our results are consistent with available experimental data and help to elucidate the selectivity filters in the Mg²⁺-selective TRPM6 and CorA channels.