Permeation of organometallic compounds through phospholipid membranes
The aim of this thesis was to investigate the permeation of small organometallic molecules through a membrane computer model at a molecular level by means of molecular dynamics simulations. As a first step, a realistic model for a typical biological membrane was developed. As phospholipid bilayers provide simple but very informative model systems, a pure phospholipid bilayer system, containing a single type of phospholipid (dipalmitoylphosphatidylcholine or DPPC), was simulated in the biologically relevant liquid crystalline state. The simulated DPPC membrane patch consists of 200 lipids (100 per leaflet) and about 5800 water molecules. Emphasis was laid on properties that are thought to play an important role in permeation processes, such as membrane density, ordering degree of the lipid acyl chains, or lipid mobility. As a second step, the permeation processes of a dimethylarsinic acid and trimethylbismuthane through the DPPC membrane model were studied. These compounds were chosen because they are one of the simplest widely distributed in nature organometallic compounds, containing arsenium and bismuth. As permeation processes are too slow on the time scale accessible to the molecular dynamic technique, they cannot be directly followed. Equilibrium molecular dynamic simulations were first carried out to gain insight into the solute partitioning behavior within the membrane. Non-equilibrium simulations, based on the average force method, were then undertaken to quantify the free energy barrier to be overcome by the permeants for their translocation from the water phase into the membrane interior. As organometallic compounds are poisonous, obtained results could be used to understand the ways of permeation of these compounds in all live organisms and are useful for evaluation of the impact of these compounds on the cells. From a second point of view, some organometallic compounds are used as anticancer drugs and the knowledge of permeation processes could be used during drug design stage in order to develop the appropriate drug molecule, which can easily permeate through the cell membrane while keeping maximum anticancer impact.
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