In this project funded by the Chemical Structure, Dynamics & Mechanism B Program of the Chemistry Division, Professor Chengshan Wang of the Chemistry Department at Middle Tennessee State University is studying the structure of aggregates of a protein, alpha-synuclein, that is abundant in the human brain and that has been linked to Parkinson's disease. Alpha-synuclein forms two types of aggregates: mature fibrils and oligomers. The mature fibrils are known to be non-toxic, but oligomers can cause the death of the neuronal cells by forming pore structure in the cell membrane. Understanding the structure of oligomer aggregates should provide clues for the development of therapeutic agents for Parkinson's disease. Undergraduate and graduate students working on this project include first-generation and underrepresented minority students who are learning about research areas that could influence their career choices. In addition, a new laboratory experiment on peptide synthesis for a graduate level organic chemistry class is being developed.
Various techniques have been developed to determine the structure of proteins. Among them, Fourier transform infrared spectroscopy (FTIR) provides a fast response and has been used to evaluate various conformations (such as alpha-helix, beta-sheet, unstructured conformation) in proteins and peptides. This method utilizes the amide I band, which arises from the stretching mode of the carbonyl group in the backbone amide bonds. Traditional FTIR can only provide information about an overall fraction of the conformations. To expand its capability, 13C labels can be introduced to the carbonyls in the backbone amide bonds and a new band (the 13C amide I band) can be generated to determine the conformation of specific residues. In this project, 13C labels are introduced into the sequence of alpha-synuclein to study the conformation of the oligomers of alpha-synuclein at the residue level. In addition, Infrared Reflection-Absorption Spectroscopy is used to address the orientation of 13C labeled carbonyls. With both conformation and orientation information, the structure of alpha-synuclein can be evaluated in phospholipid bilayer structures.
