Why Cellular Di/Triphosphates Preferably Bind Mg²⁺ and Not Ca².

Area of Science:

• Biochemistry
• Computational Chemistry
• Molecular Biophysics

Background:

• Di/triphosphates are crucial components of vital organic cofactors like ATP/GTP.
• These phosphates typically bind to cations, especially Mg²⁺, within cells.
• The precise metal-binding modes and competitive interactions between Mg²⁺ and Ca²⁺ for these phosphates are not fully understood.

Purpose of the Study:

• To investigate the binding modes of di- and triphosphate groups with Mg²⁺ and Ca²⁺.
• To determine the factors influencing the competition between Mg²⁺ and Ca²⁺ for these phosphate ligands.
• To elucidate why Mg²⁺ is preferentially used in biological processes involving triphosphates.

Main Methods:

• Density functional theory (DFT) calculations were employed.
• A polarizable continuum model (PCM) was utilized to simulate cellular environments.
• Relative free energies and binding stabilities were calculated for various binding modes.

Main Results:

• The competition outcome depends on the phosphate ligand's charge, binding mode, and solvent exposure.
• Increased phosphate denticity (bi- to tridentate) in buried sites favors binding of the stronger acceptor, Mg²⁺.
• Cellular conditions, including higher Mg²⁺ concentration and protein matrix interactions, favor Mg²⁺ binding.

Conclusions:

• Mg²⁺'s preference for di/triphosphates is explained by ligand properties and cellular concentrations.
• The study provides insight into nature's selection of Mg²⁺ over Ca²⁺ for essential triphosphate-related biological functions.
• Understanding these interactions is key to comprehending cellular energy transfer and signaling pathways.