Passive transport of charged molecules through membranes

By Martin Vlaar

Membranes are laminar structures formed by self-assembly of phospholipids. In nature they are found in all cells, where they separate the interior of a cell from the outside. Due to their special structure with the hydrophobic tails of the lipids pointing towards the inside of the membrane while the hydrophilic head groups of the lipids point towards the outside, membranes are thought to act as a nearly impenetrable barrier for polar molecules or charged ions. Nowadays we know however that once in a while, some polar molecules or ions may overcome the high-energy-barrier and cross the membrane. Some molecules do this faster than others. The permeability rate of protons, for example, is orders of magnitude higher than that of equally charged and equally sized sodium ions. The reason behind this behavior is still not understood, and several different transport models have been proposed, but no model can fully explain for this difference.

There is both a fundamental and a practical reason why people are interested in these membrane transport phenomena. In the first steps of evolution, primitive cells were formed by self-assembled membranes. During later steps, however, to enter the primitive cell molecules had to cross the membrane without help of transport proteins, which were not formed yet. Knowledge of these processes may clarify the behavior of nature in the early stages of life. A better understanding may also lead to new or better pathways of drug delivery and several other pharmaceutical applications.

My research aims at getting a better knowledge of the molecular mechanism of the transport of protons and other ions through membranes and finally explain for the difference in permeability rates for different ions. The membrane system will be modeled by Molecular Dynamics (MD); the forces between atoms are calculated and by integrating the equations of motion the velocities and positions from atoms can be calculated during different time steps. Because the ions have to cross such a high barrier, it takes ages to finally sample a transport event. Therefore we need to help the system to overcome this barrier. One way to do this, is Transition Path Sampling (TPS). The system is brought in a random state between the initial and final state. From this state the trajectories of the atoms are calculated in the past and in the future. When the past trajectory ends in the initial state while the future trajectory ends in the final state we obtain a transition path. This may lead to an ensemble of transition paths from which the most probable one can be calculated. This path will say something about the molecular mechanism.