Lipid bilayer permeation of an aliphatic amine drug: modeling with molecular dynamics simulations and kinetic rate equations
Oruç, Tuğçe (2016) Lipid bilayer permeation of an aliphatic amine drug: modeling with molecular dynamics simulations and kinetic rate equations. [Thesis]
Aliphatic amine bearing drugs constitute about 27% of all orally active drugs. Since they comprise a large proportion, it is important to understand their permeation mechanism through cell membrane. In this thesis, the permeation of an aliphatic amine drug through a lipid bilayer is treated at three different levels of spatio-temporal resolution. On the finest scale, the interactions of the aliphatic amine drug dyclonine with the lipid bilayer are modeled in atomistic detail via molecular dynamics (MD) simulations. Because the aliphatic amine group is ionizable it can be in either positively charged or neutral. MD simulations reveal that both charge states penetrate into the bilayer and the neutral drugs easily translocate. However, complete permeation events are not observed. To understand the mechanism of permeation, therefore, a coarser model of one-dimensional diffusion in a potential is employed. To apply the model, diffusivity and free energy profiles along bilayer normal are obtained via MD simulations. The resulting hydrodynamic description of the permeation allows access to longer time scales and provides the calculation of the permeability coefficients. Finally, on the coarsest level, we model the drug permeation into liposomes via kinetic rate equations. The model reproduces recent experiments that measure the permeability coefficients of aliphatic amine drugs using pH-sensitive fluorophores. We observe that while the experimental assay is sensitive to the protonation rate of the drug, it is basically insensitive to the drug permeability. The multiscale modeling strategy employed here is very general and can be straightforwardly applied to other titratable drug molecules.
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