Influence of the dimensionality of the periodic boundary conditions on the transport of a drug–peptide complex across model cell membranes

Abstract

Many research efforts are devoted to improving the efficiency of chemotherapy. One of the aspects is to facilitate the transport of drugs across the cell membranes by attaching the therapeutics to a carrier molecule. The current study focuses on computational investigation of such a system with doxorubicin as the model drug, which is covalently bound to a cell-penetrating peptide. The correct description of its membrane translocation at the molecular level requires proper choice of the model membrane and of the simulation parameters. For the purpose, two phospholipid bilayers are built, one containing solely DPPC and another with mixed lipid content mimicking the composition of a human erythrocyte membrane. Atomistic molecular dynamics simulations are carried out in two types of periodic boundary conditions (2D and 3D PBC), in order to assess the effect of the periodicity dimensionality on the intermolecular interactions. The evolution of some basic characteristics of the bilayers and of the drug–peptide complex is tracked: mass density profiles, electrostatic potentials, lateral diffusion coefficients and areas per lipid, lipid-complex radial distribution functions, secondary structure of the peptide and orientation of the drug relative to the membrane. Thus, the influence of the periodic boundary conditions is quantified and it shows that the mixed system in 3D PBC is the most suitable for analysis of the translocation of the transporting moiety across cell membranes.

Graphical Abstract

The type of periodic boundary conditions, three-dimensional vs. two-dimensional (3D vs. 2D PBC), causes marked influence on the process of membrane penetration of doxorubicin carried by a cell-penetrating peptide, as evidenced by 1-µs-long atomistic MD simulations.

Communicated by Ramaswamy H. Sarma

Keywords:

• Lipid bilayer
• phospholipids
• 2D vs. 3D periodic boundary conditions
• mass density profiles
• supramolecular order
• DOX–CPP complex
• membrane transport

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The research has been partly co-funded by the European Commission program Horizon 2020 under project ‘VI-SEEM’, Grant Agreement N^o: 675121 (computational time on the HPC facility Avitohol within the framework of the application MULTIDRUG).