Proteins and protein interactions are fundamental components of biological processes. Using molecular dynamics, the physical properties of proteins at various stages, and their association with functional or disease-causing complexes, can be probed under conditions that are difficult to investigate experimentally.

The first project presented in this work addresses the transition of the protein Serum amyloid A into a disease-causing conformation. Serum amyloid A is an acute phase protein and as such responds to trauma in the body. When incorrectly folded the protein may form amyloid fibrils which leads to severe diseases. Therefore, it is important to understand the transition from the normal to the pathological conformation. An advanced sampling technique, Replica Exchange with Tunneling (RET), was used for this purpose and it was established that there is a low energy barrier between the two forms of the protein and that the transition depends on the unfolding of the N-terminus of the protein.

The second project is motivated by the search for antibiotics. Because of its ability to form pores in membranes, nisin is pernicious to bacterial cells; however, the mechanism by which the pores are formed and are stabilized is unknown. Additionally, instability and insolubility at physiological conditions limit the broader use of the protein as an oral drug. To investigate the pore formation mechanism of nisin in bacterial cells and how the pores affect the integrity of the membranes, all atomistic molecular dynamics simulations were performed. It was determined that residues 8-28 of nisin are important for the stability of the pore and that in the presence of lipid II, a component of the bilayer that is specific to bacteria cells, the pore is more stable. The integrity of the membrane is further reduced by local changes in thickness and viscosity.

In addition to having antimicrobial properties, nisin can inhibit cancer growth but does not appear to harm healthy human cells. As cancer cell membranes do not contain the bacteria-specific lipid II, there must be different mechanisms by which nisin induces cell death in cancer and bacteria cells. The third, and yet unfinished, project compares the interaction of nisin with different types of cell membranes – bacteria, cancer, and eukaryotic cells. Furthermore, simulating nisin in membrane environments allows for a more general inquiry into the not-well-understood physical dynamics of membranes. This is a promising area for future studies.