Structural Transitions in Proteins and Protein Assemblies Project Summary/Abstract A detailed knowledge of the relation between chemical composition and structure/function of proteins is crucial for an understanding of disease pathways and the working of drugs at the level of cells. De- spite decades of research, both experimental and computational, this relationship is still only partially understood. In the present project, we develop advanced computational methodologies to investigate structural changes that are dif?cult to probe in experiments, but are important because they change the function of proteins, or the toxicity of protein aggregates. These techniques are tested and opti- mized in studies of two proteins, RfaH-CTD and lymphotactin, that change their function by switching between two different structures. While focusing on simple model systems, the gained insight may guide therapeutic applications, for instance, the design of components that stabilize a certain confor- mation. In a second set of simulations we extend our techniques and concepts to the oligomerization of amyloid-forming A -peptides, implicated in Alzheimer's disease. Combining our computational studies with experimental investigations by the Rangachari Lab at University of Southern Mississippi, we will study the transition between toxic and non-toxic (or less toxic) aggregates, and why some amyloids can seed their own growth by converting other forms. Understanding this process may in turn lead to the development of drugs that modulate the spread of such ?infectious strains?.
Structural Transitions in Proteins and Protein Assemblies Project Narrative New simulation techniques are developed for the study of folding and aggregation of proteins that are observed in more than one structure. These techniques are tested and optimized in simulations of two proteins that alter their function by switching between two structures, and applied to probe the mechanism by that certain aggregates can auto-catalyze their growth and become?infectious strains? in amyloid diseases.
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