Charge of calcium chloride12/27/2023 Many studies demonstrated that calcium binds primarily to phosphate groups of all phospholipids, independent of their charge 28, even in pure PC membranes 17, 29, 30. Experimental methods, predominantly NMR-based, identified two distinct binding modes of calcium to PC/PS membrane, but their nature is not completely resolved 20, 27. In this system, three possible binding sites can be distinguished: carboxyl groups of PS, phosphate groups of PC and PS, and carbonyl groups of PC and PS. Lipid bilayers consisting of 80 mol% phosphatidylcholine (PC) and 20 mol% phosphatidylserine (PS) have often been used as a simple model of the inner leaflet of the plasma membrane. Since physiological concentrations of calcium are low and calcium domains are highly localized in space, the global membrane changes induced by its binding are highly relevant as well as the identity of the local binding sites. Conformational changes of the lipid headgroup region 20, 21, ordering of acyl chains 20, 21, 22, and lipid dehydration 17, 23, 24, 25, 26 were reported. It is generally accepted that the presence of Ca 2+ rigidifies and orders lipid bilayers 13, 15, 16, 17, 18, 19. The interactions of calcium ions with lipid membranes have been probed by a variety of experimental methods 11, 12, 13, 14. Ca 2+-membrane binding is also recognized as a key factor during membrane fusion 10. Calcium ions can also serve as a bridge between a protein and the cell membrane, for instance, during membrane association of C2 domains and annexins 8, 9. Recently, it has been shown that adsorption of calcium can neutralize this negative charge, and that this effect alone is responsible for the modulation of T-cell activation 7. Namely, apart from protein-based buffers, calcium ions strongly interact with the negatively charged inner leaflet of the plasma membrane 6. There is one commonly overlooked factor that significantly influences behavior of calcium ions upon their influx into the cytosol. These spikes can be up to 100-fold higher compared to the resting Ca 2+ concentration and are both spatially and temporally modulated by the calcium buffers 4. On the other hand, key events in calcium signaling are connected with rapid spikes of Ca 2+ concentration caused by an influx of the Ca 2+ into the cytosol via calcium channels 5. The maintenance of low intracellular calcium concentrations is achieved, among other mechanisms, by calcium buffers which include both cytoplasmic and membrane-anchored calcium-binding proteins 1, 3, 4. The concentration of Ca 2+ in the extracellular space is about 2 mM, while its intracellular levels are much lower and range amongst cell organelles from 100 nM in the cytosol to 600 μM in the endoplasmic reticulum 1, 2. Their divalent character makes them strong binders hence, their physiological concentration must be strictly controlled. Similar content being viewed by othersĬalcium cations are very potent and versatile agents within a cell. Significantly, the binding mode depends on calcium concentration with important implications for calcium buffering, synaptic plasticity, and protein-membrane association. We demonstrate that lipid membranes have substantial calcium-binding capacity, with several types of binding sites present. To gain additional atomic-level information, the experiments are complemented by molecular simulations that utilize an accurate force field for calcium ions with scaled charges effectively accounting for electronic polarization effects. Namely, time-resolved fluorescent spectroscopy of lipid vesicles and vibrational sum frequency spectroscopy of lipid monolayers are used to characterize local binding sites of calcium in zwitterionic and anionic model lipid assemblies, while dynamic light scattering and zeta potential measurements are employed for macroscopic characterization of lipid vesicles in calcium-containing environments. We quantify these interactions in detail by employing a combination of spectroscopic methods with atomistic molecular dynamics simulations. Understanding interactions of calcium with lipid membranes at the molecular level is of great importance in light of their involvement in calcium signaling, association of proteins with cellular membranes, and membrane fusion.
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