Peptide Assembly:Mechanism and Inhibition

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The award CHE-1301032 provided by the Chemical Structure, Dynamics and Mechanism-B Program (CSDM-B) and the Chemistry of Life Processes of the National Science Foundation to Professor Michael T. Bowers at the University of California at Santa Barbara will be used to investigate the mechanism of peptide assembly. This is currently a very active area of research both for its fundamental importance and because of possible therapeutic applications in neurological diseases. These studies will include the determination of oligomer distributions, the structures of sized selected oligomers and the effect of select inhibitors on this process. Peptides will be selected to test existing models for beta sheet formation and eventual fibrilization and for their possible implications in amyloid based diseases. Experimental methods will include ion mobility spectrometry coupled with mass spectrometry, atomic force microscopy and transmission electron spectroscopy and a newly developed oligomer size selected infrared spectroscopy experiment constructed at the Fritz Haber Institute in Berlin, Germany. The experiments will be complimented by high level theoretical calculations including both DFT and replica exchange molecular dynamics. Inhibitors will include both naturally occurring substances like polyphenols and specially synthesized molecules designed for select peptide attachment. The two fastest growing major diseases in the US today are Alzheimer's disease and Type 2 Diabetes. These seemingly dissimilar diseases share the common trait of having toxic agents that come from the assembly of ordinarily innocuous agents (peptides) in the body: one process occurring in the brain causing Alzheimer's disease and the other in the pancreas causing Type 2 Diabetes. It isn't clear how these normally safe species assemble into deadly ones nor is it clear how they kill cells once they do assemble. This is a difficult problem to study with the normal tools of biochemistry that can't select specific assembled peptides and hence can't tell their structure or how toxic they are. The thrust of this proposal is to provide a new set of methods that can do this selecting and to apply these methods to model peptide systems to learn the factors that control peptide assembly in general and then test simple molecules that can stop this assembly in its tracks. Finally the results are translated into presentations that can be given to local high schools and each Bowers group member visits several such schools each year to make these presentations.