Understanding the Critical Step for the Cellular Toxicity of Protein Oligomers.

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Protein molecules have evolved to attain functional and soluble states under normal and physiological conditions. In some cases, however, some protein molecules are unable to remain stable as monomers and consequently associate into protein aggregates having a fibrilar nature. These aggregates, designated as amyloids, have a large biological relevance and are in fact considered attractive structures for targeting new generations of biomaterials. Early states of amyloids, namely protein oligomers, are important biological targets as they can be inherently toxic. Understanding the bases of the oligomers toxicity is essential to develop the next generation of biomaterials as well as to understand the nature of some aberrant diseases that are connected to the amyloid formation, including Alzheimer's, Parkinson's and type II diabetes. An crucial step that defines the biological properties of protein oligomers is the interaction with the cell membrane. This interaction represents the key event in the toxicity of protein oligomers. Understanding the molecular basis of the interaction with the membrane will provide a significant step forward in our understanding of the biology of protein oligomers. Many aspects of this interaction are currently unknown. What makes a prefibrilar oligomer toxic? Why only some protein oligomers are able to penetrate the membrane? How the membrane properties dictate the interplay with protein oligomers?The present project will provide a novel and innovative platform of experiments and theory to investigate in detail on the structural nature of prefibrilar protein oligomers. The project will shed light in the selective interaction with phospholipid membranes that distinguishes between toxic and non-toxic oligomers. To this aim, the research will combine cutting-edge experiments of nuclear magnetic resonance with advanced molecular computation. Thus, in addition to the specific biological target of tackling the molecular origins of the oligomers toxicity, this research will extend our ability to study complex molecular mechanisms, with a large number of applications ranging from structural biology to synthetic and system biology and to material sciences.