LIPID BILAYER PERMEATION OF AN ALIPHATIC AMINE DRUG:
MODELING WITH MOLECULAR DYNAMICS SIMULATIONS AND KINETIC RATE EQUATIONS
Biological Sciences and Bioengineering MSc. Thesis , 2016
Assist. Prof. Dr. Deniz Sezer (Thesis Advisor),
Prof. Dr. Canan Atılgan,
Assoc. Prof. Dr. Elif Özkırımlı Ölmez
Date & Time: June 1st, 2016 – 11:00 AM
Place: FENS G032
Keywords : Drug Permeability, Aliphatic Amines, Molecular Dynamics Simulations, Kinetic Modeling
Aliphatic amine bearing drugs constitute about 27\% of all orally active drugs. Since they comprise a large proportion of the drugs in the market, it is important to understand their permeation mechanism through cell membranes in detail. In this thesis, the permeation of an aliphatic amine drug through a lipid bilayer model of the cell membrane 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 for neutral depending on the pH of the environment. The conducted MD simulations reveal the critical importance of the charge for the solubility of the drug molecules in water and for their insertion into the lipid bilayer. They also demonstrate that the neutral drug molecules easily translocate between the two leaflets of the lipid bilayer. However, complete permeation events - including drug insertion into, translocation across, and dissociation from the lipid bilayer - are not observed in the MD simulations. To gain access to the mechanism of permeation, therefore, a coarser model of one-dimensional (1D) diffusion in a potential is employed. While focusing only on the motion of the drug molecules along the direction perpendicular to the plane of the lipid bilayer, this model assumes that the profiles of diffusivity and free energy that each drug encounters during its permeation are known. Here, these profiles are obtained from MD simulations. The resulting hydrodynamic description of the permeation process allows access to longer time scales and makes possible the calculation of the permeability coefficients of the neutral and charged drug molecules. Finally, on the coarsest level, we model the permeation of the protonated and deprotonated drug molecules into spherical liposomes via kinetic rate equations. Kinetic models of increasing complexity are constructed in an effort to reproduce recent experiments that measure the permeability coefficients of aliphatic amine drugs using pH-sensitive fluorophores encapsulated in liposomes. We observe that while the experimental assay is sensitive to the protonation rate of the drug (and the fluorophore), it is basically insensitive to the drug permeability.
The multiscale modeling strategy employed here to study the membrane permeation of the aliphatic amine drug dyclonine is very general and can be straightforwardly applied to other titratable drug molecules, including aliphatic amines and carboxylic acids. It has the ability to establish a quantitative link between the molecular properties of these drugs and their membrane permeability. The kinetic modeling, which forms the coarsest level of the presented computational approach, covers time scales of direct bearing to physicochemical experiments with titratable drugs. Our findings argue for its wider use in the interpretation and quantitative analysis of data from such experiments.