Free energy calculations on calcium and magnesium complexes: Protein and phospholipid model systems

Free energy calculations have been performed on a variety of calcium (Ca(II)) and magnesium (Mg(II)) complexes as model systems for protein-metal, phospholipid-metal, and protein-metal-phospholipid interactions. The major goal of this work was to advance our understanding of Ca(II) ion selectivity in the blood coagulation proteins. The limitations of present force field methods as applied to divalent metal ion-containing systems is discussed. The effects of different water models, varying nonbond cutoff values, and counterions are evaluated. Additionally, the effects of complete charge transformation between predetermined quantum mechanical states is evaluated in which all of the charges of the metal complexes as well as the van der Waals radii of the metals are perturbed. Protein models include formate, malonate, ethylene-diaminetetraacetate, and 1,1,4,4-butanetetracarboxylic acid. Phospholipid mimics included methylphosphatidylserine, methylphosphatidylcholine, dimethyl phosphate, and trans-cyclohexane-1,3-diphosphate. The present set of calculations tends to overestimate Mg(II) binding in the various test systems for which experimental results exist, an effect which may in part be due to the lack of explicit polarization/charge transfer terms for all molecules, including water, in the force field. However, these calculations support the notion that coagulation protein selectivity towards Ca(II) is likely due to a greater ease of desolvation of Ca(II) over Mg(II).