Thermodynamics and Intermolecular Interactions during the Insertion of Anionic Naproxen into Model Cell Membranes

The insertion process of Naproxen into model dimyristoylphosphatidylcholine (DMPC) membranes is studied by resorting to state-ofthe-art classical and quantum mechanical atomistic computational approaches. Molecular dynamics simulations indicate that anionic Naproxen finds an equilibrium position right at the polar/nonpolar interphase when the process takes place in aqueous environments. With respect to the reference aqueous phase, the insertion process faces a small energy barrier of approximate to 5 kJ mo1(-1) and yields a net stabilization of also approximate to 5 kJ mol(-1). Entropy changes along the insertion path, mainly due to a growing number of realizable microstates because of structural reorganization, are the main factors driving the insertion. An attractive fluxional wall of noncovalent interactions is characterized by all-quantum descriptors of chemical bonding (natural bond orbitals, quantum theory of atoms in molecules, noncovalent interaction, density differences, and natural charges). This attractive wall originates in the accumulation of tiny transfers of electron densities to the interstitial region between the fragments from a multitude of individual intermolecular contacts stabilizing the tertiary drug/water/membrane system.

Automated summary

The insertion process of Naproxen into DMPC membranes was studied using molecular dynamics simulations and quantum mechanical computational methods. The insertion process faces a small energy barrier and is mainly driven by entropy changes due to structural reorganization. The formation of an attractive fluxional wall of noncovalent interactions is crucial for stabilizing the tertiary drug/water/membrane system.