Atomistic simulations of tight junction proteins

The surface cells of the body are joined together by specific junctions, some which keep the cells together (adherens and desmosomes) and others that prevent or regulate flow of molecules between the cells. The latter are the so called tight junctions. Tight junctions (TJs) limit the passage of permeants through the inter-cellular space between adjacent epithelial and endothelial cells (Zihni, Mills, Matter, & Balda, 2016). They act as either barriers or selective gates, allowing the permeation of molecules in a size and charge selective way and help multicellular organisms maintain homeostasis. The primary proteins involved are the claudins. Claudin 1, the primary protein of interest here, is a ubiquitous claudin found in most tissues and located in the skin’s epidermis layer contributing in the skin barrier (Günzel & Alan, 2013). Claudins are transmembrane proteins and have external loops which come together to form the barrier or selective gate. The barrier function of TJs is regulated by the specific cisinteractions (in the same cell membrane) and trans- interaction (on adjacent cells membranes) of TJ proteins. The interaction can be either homo- or hetero- depending on whether it is between same or different proteins respectively. The fundamental question is how do these proteins interact at a molecular level resulting in the formation of the barrier? We need to get a better understanding of the assembly of the TJ proteins, their resulting architectural organisation, and the molecular level mechanism of the barrier function (Krause, Protze, & Piontek, 2015). In attempting to understand the assembly and resulting architecture of the TJ proteins, the atomistic resolution offered by molecular dynamics simulations can add considerable value. A molecular dynamics simulation of a system of molecules yields trajectories of the behaviour of molecules. The simulations yield structural information, dynamics and thermodynamic quantities characterising the system. The project investigates the behaviour of the extracellular loops (ECLs) of claudin 1 via their simulation in a box containing water and counterions. Subsequently, multiple loops are aligned in space as if they were attached to membranes as in cells. The loops are left to interact freely in the environment that imitates their natural one and analyse their selfassemble into higher order structures. Through these simulations, we should be able to investigate the packing of the ECLs and where appropriate investigate the nature of the selectivity with respect to permeability (Anderson & Van Itallie, 2009). Furthermore, we anticipate to model interactions of proteins with other molecules that can compromise the barrier