Molecular modelling of ion transport and toxin binding in sodium channels

Ion channels are membrane proteins that play an important role in the transmission of electrical signals in cells. The binding of a ligand or an electrical signal to the ion channels allows these channels to open as the membrane potential chan-ges. These channels allow certain type of ion such as Na+, K+, Ca2+ or Cl- to across from the cell membrane. These channels work like transistors in electronic circuits. While this occurs in many cell signals, the most basic is the transmission of the action potential in nerve cells. Functional disorders that occur in the ion channels due to mutation of channel proteins that occur in gene codes or environmental effects have been associated with many diseases. So ion channels are an important target for therapeutic drugs. Structural information is the basis for model work, but it is not enough to fully understand how the channels work. While many features of channel functions can not be reached directly experimentally, computer-aided simulations can provide information on structure and function of channel proteins. In this work, ion transition mechanism of sodium voltage-gated ion channels with crystal structure was tried to be elucidated by molecular dynamics simulations. At the same time, free energy calculations were carried out to investigate ligand binding to these channels. Free energy calculations will be obtained from the calculation of the force field potential (PMF) using the Umbrella Sampling Method over a selected reaction coordinate. The Umbrella Sampling Method is a simulation method applied over predefined reaction coordinates.The free energy profile is also passed from the WHAM analysis. In this method, a large number of simulations are run at different locations of the umbrella potential along the reaction coordinates. The population values represented by the potential energy applied from the samples of each simulation are revealed. The resulting population (density function) is combined along the reaction coordinate using the Weighted Histogram Analysis Method. In addition, studies have also been conducted on homology modeling of the Nav1.4 channel from mammalian sodium voltage-gated ion channels for which crystal structure has not been revealed. The complex structures and free energy calculations obtained as a result of the studies carried out provide detailed information on the binding sites of sodium ions and also provide information on ion coordination and ion permeability. It is believed that inhibition of the sodium channels of the results obtained by ligand binding will be explained and that these channels will be useful in the development of blocking drugs in order to be a template.