DNA–phospholipid recognition: modulation by metal ion and lipid nature. Complexes structure and stability calculated by molecular mechanics

The structures and formation energies of nucleic acid–phospholipid complexes both in the absence and in the presence of Mg2+ ions were calculated taking double-stranded trinucleoside diphosphates NpNpN or heptanucleotides ApAp(NpNpN)pApA, composed of 64 possible combinations of genetic code, and phosphatidylcholine (PC) and sphingomyelin (SM) as model compounds. The dependence of intramolecular interactions on the primary structure of nucleic acid molecules and on the presence of a cationic bridge was revealed. The formation energies and structure of oligonucleotides were found by molecular mechanics calculations with the AMBER force field. The structures of phospholipid and MgCl2 molecules were calculated by the semiempirical PM3 method, while the energies of phospholipid–oligonucleotide complexes were calculated by the molecular mechanics method. Calculations of complexes were carried out with consideration of solvation effects. Considerable gain in the formation energy of triple complexes is achieved due to the presence of the electroneutral metal bridge. A tendency toward increasing the stability of “triple” PC complexes (but not SM ones), containing guanosine- and cytidine-enriched triplets was revealed. Depending on the structure of NpNpN trinucleotides, the formation energy values of NpNpN–MgCl2–PC and ApAp(NpNpN)pApA–MgCl2–PC complexes differ by 1.7–2.6 kcal mol−1, which can be considered as the atomic-scale manifestation of the recognition phenomenon. Presence of metal (II) ion bridge results in a greater stabilization of the phospholipid–nucleic acid complexes for SM in comparison to PC (the total energy difference equals to 4–16 kcal mol−1). Depending on the structure of NpNpN trinucleotides, the formation energies of NpNpN–MgCl2–SM and ApAp(NpNpN)pApA–MgCl2–SM complexes differ by 1.7–2.1 kcal·mol−1, which is essential at physiological conditions and can also be considered as the recognition effect.