Intrinsically Disordered Proteins

In the aging population of the Western World, age-related neurodegenerative diseases, such as Alzheimer's and Parkinson's, are becoming an ever-increasing issue. Common to these diseases are build-up of protein matter in the brain, leading to degeneration of brain tissue. The proteins responsible for this degeneration belong to a group of proteins usually found on the periphery of structural biology; the intrinsically disordered proteins (IDPs). Lacking the structural elements traditionally associated with function, IDPs were historically ignored by structural biologists as "non-functioning". In the modern age of proteomics, this group of proteins has indeed proven to be functional, but in connection with disease, it is the sudden malfunction of IDPs that is in focus.

As this group of proteins lack classically defined structural elements and are highly dynamic, the usual structural characterisation tools fall short in the analysis of IDPs, and even our fundamental understanding of "structure" fails. It is therefore imperative to develop new tools, and to generate a new understanding of protein structure itself when analysing IDPs.

In the TSM² group, we do exactly that: By combining state-of-the-art chiroptical spectroscopic techniques with cutting-edge computational chemistry, the world of the IDPs is analysed in detail, redefining what constitutes protein structure and ultimately aiding the understanding of what turns a normal, functioning IDP into a pathogenic entity. Raman optical activity (ROA) spectroscopy is uniquely sensitive to the local structure of proteins and peptides. By using density functional theory calculations, the experimental ROA patterns of proteins are analysed in detail. Establishing the relation between the structural elements of proteins and the corresponding spectral components, the solution structure and dynamics of IDPs can be studied.