Classical and enhanced molecular dynamics simulations to explore the dynamics of drug binding to membrane proteins

Abstract

The ability to determine drug binding modes can drive rational drug development and drug discovery initiatives. A key component of this is the dynamics of the drugs and the protein which may be captured in molecular dynamics simulations. Classical and several enhanced molecular dynamics protocols have emerged over the decades with varying degrees of applicability for determining drug binding modes. Apart from these techniques, there are numerous factors to consider in simulations from the initial simulation conditions to the choice of molecular mechanics force field. These non-trivial choices dictate the value of MD simulations in understanding drug binding modes and ultimately its ability to contribute to drug discovery initiatives. In this thesis, we apply a variety of molecular dynamics methods to investigate the binding of drugs to three distinct membrane proteins. These comprise the Mycobacterium tuberculosis MurX enzyme, the human oxytocin receptor, a G-protein coupled receptor and the human nicotinic acetylcholine receptor, a ligand gated ion channel. For each protein, we critically examine the selected methods by their ability to provide drug binding modes in agreement with experimental data. This critical assessment should drive more efficient and informed molecular dynamics research into understanding drug binding modes.