Developing an in silico model
of solute transport
across a lipid bilayer model of the blood–brain barrier and
benchmarking simulations. (A) Schematic illustration of the luminal
and abluminal membranes of a brain microvascular endothelial cell.
Passive transport into the brain involves diffusion across both membranes.
(B) Overlays from a simulation showing the location of a solute during
translocation across the lipid bilayer. The lipid bilayer consists
of nine lipids: POPC (dark gray), OSM (red), SAPE (purple), SAPS (brown),
SAPI (orange), cholesterol (green), SAPC (cyan), SOPE (black), and
SLPC (magenta). Atomic detail models were constructed using the CHARMM-GUI
membrane builder. (C) Molecular dynamics simulations of BBB permeability
showing the real computational time (in months) to simulate solute
transport at 310 K using a modern graphics processing unit (GPU) based
on a solution volume of 100 nm3 and a bilayer area of 25
nm2. We assume that 100 translocation events are necessary
to determine the steady-state permeability, and that simulation of
100 ns takes 1 day. Experimental values of solute permeability range
from about 10–6 cm s–1 (slowest)
to 10–3 cm s–1 (fastest). (D)
Relationship between bilayer dimensions and computational time, with
smaller bilayer areas enabling longer simulation times.