The intermolecular interactions established between anticancer drugs and lipid membranes play a key role in the permeation mechanism of the drugs inside the cells. Herein we extend a quantum mechanical energy decomposition analysis scheme based on deformation electron densities to a hybrid multiscale quantum mechanics/molecular mechanics (QM/MM) framework, and apply it to characterize the interactions between the cisplatin drug and a dioleyl-phosphatidylcholine lipid membrane. The interaction energy decomposition into electrostatic, induction, dispersion and Pauli repulsion contributions is performed for ensembles of geometries taken from molecular dynamics simulations to account for conformational sampling and, thus, obtain a distribution of each of the energy components. Contrary to a previous energy decomposition using force fields, it is evidenced that the electrostatic component is predominant in both polar and non-polar regions of the bilayer, and the repulsive component is strong when considered quantum mechanically, while being largely underestimated by the force field
Supporting Information for Characterization of Cisplatin/Membrane Interactions by QM/MM Energy-Decomposition Analysis
Energy decomposition analysis equations, computational details and correlation coefficients for the energy components with respect to the interatomic distances.