Estimation of Liposome Penetration Barriers of Drug Molecules with All-Atom and Coarse-Grained Models

Liposomes are common
carriers of drug molecules, providing enhanced
delivery and accumulation of hydrophilic agents or larger biomolecules.
Molecular simulations can be used to estimate key features of the
drug molecules upon interaction with the liposomes, such as penetration
barriers and localization. Herein, we investigate several aspects
of the computational estimation of penetration barriers, viz. the potential of mean force (PMFs) along a vector spanning the
membrane. First, we provide an evaluation of the all-atom (AA) and
coarse-grained (CG) parametrization of 5-aminolevulinic acid (5-ALA)
and two of its alkyl esters by computing n-octanol/water
partition coefficients. We find that the CG parametrization of the
esters performs significantly better than the CG model of 5-ALA, highlighting
the difficulty to coarse-grain small, polar molecules. However, the
expected trend in partition coefficients is reproduced also with the
CG models. Second, we compare PMFs in a small membrane slab described
with either the AA or CG models. Here, we are able to reproduce the
all-atom PMF of 5-ALA with CG. However, for the alkyl esters it is
unfortunately not possible to correctly reproduce both the depth and
the penetration barrier of the PMF seen in the AA simulations with
any of the tested CG models. We argue that it is more important to
choose a CG parametrization that reproduces the depth of the PMF.
Third, we compare, using the CG model, PMFs in the membrane slab with
PMFs in a large, realistic liposome. We find similar depths but slightly
different penetration barriers most likely due to differences in the
lipid density along the membrane axis. Finally, we compute PMFs in
liposomes with three different lipid compositions. Unfortunately,
differences in the PMFs could not be quantified, and it remains to
be investigated to what extent liposome simulations can fully reproduce
experimental findings.