Peptide folding and local unfolding of SOD1 in the presence of interacting macromolecular crowders - a Monte Carlo approach
Abstract: A protein chain often folds into a functional, specific three dimensional structure. Failurein this process can in some cases lead to disease, e.g. the misfolding disease ALS. Themechanisms behind the folding has mostly been studied under dilute conditions. However,in the natural cellular environment of proteins, the concentration of macromolecules is highand it is believed that this affects various processes in the cells, such as the folding, but theunderlying mechanism is largely unknown.In this thesis we present a Monte Carlo based simulation approach to study the effects ofcrowding. We investigate the equilibrium properties of two small peptides in the presenceof different types of crowders, both interacting protein crowders and non-interacting hard-spheres. In our simulations with protein crowders, we find that purely steric effects can notalone explain the observed behaviour. The peptides can be either stabilized or destabilized,depending on their specific interaction with the crowders.We also apply the same simulation scheme to study local unfolding of the ALS-linked proteinsuperoxide dismutase 1, SOD1, in the presence of crowders. We compare this with resultsobtained without crowders. The crowders are found to have little effect on the barrel stability,partly due to interaction with the functional loop regions of SOD1. In both the crowder andcrowder-free simulations, the instability of the second-sheet of the SOD1 molecule is morepronounced than that of the first sheet.Detailed knowledge of how the SOD1 molecule specifically responds to its environment opensup for the possibility to understand the mechanisms behind its misfolding, believed to beimportant in the initial events of certain forms of ALS
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