Prior x-ray diffraction, light scattering, photon correlation spectroscopy, and atomic force microscopy experiments suggest that SNARE-induced membrane fusion in cells proceeds as a result of calcium bridging opposing bilayers, which leads to the release of water from hydrated Ca²⁺ ions as well as the loosely coordinated water at PO-lipid head groups [1]. It is hypothesized that the combined effect of local dehydration of phosphate head groups, as a result of Ca²⁺ bridging, leads to a destabilization of lipid bilayers and resulting membrane fusion. This hypothesis was tested in the current study by performing atomistic molecular dynamic simulations in the isobaric-isothermal ensemble on dimethylphosphate anions (DMP^-) and Ca²⁺ in water at 298 K and 1.01 bar. Examination of molecular configurations obtained from the molecular dynamics simulations reveals the establishment of self-assembled Ca²⁺ - DMP^- complexes. Calcium ions can bridge two opposing DMP^- molecules, resulting in the formation of a somewhat ring-like structure [2].

Experimental evidence shows that other divalent cations, such as magnesium and barium, may also initiate fusion, but at slower rate [3,4]. In this study, molecular dynamics simulations were preformed to test if other divalent cations self assemble with DMP^- under same molecular dynamics conditions. Simulations show significantly fewer incidents of DMP-Mg-DMP bridges forming. Simulations of Ba²⁺ show no incidents of bridging dimethylphosphate oxygens. Radial distribution functions and number integrals show the depletion of water around DMP^- head groups and hydrated divalent cations upon bridging incidents.

Ab initio calculations were preformed to study the stability of DMP^- and its complexes with divalent cations in the presence of implicit solvent. Calculations were preformed at the B3LYP/6-31G(d,p) level of theory and CPCM solvent model. The data indicate that calcium posses a higher binding affinity to DMP^- than Mg²⁺ or Ba²⁺. Furthermore, calcium favors participating in ring complexes over forming a single bridge between two DMP^- molecules.

[1] Jeremic, A., Cho, W-J., Jena, B.; J. Biol. Phys. & Chem. 4:139-142 (2004)

[2] Potoff, J., Issa, Z., Manke, C., Jena, B., Cell Biol. Int. 00:00-00 (2008)

[3] Papahadiopoulos, D., Nir, S., Duzgunes, N.; J. Bioenergetics 22:157 (1990)

[4] Ohki, S.; Biochem et Biophys. 1:689 (1982)