Biological Applications

Protein Misfolding and Aggregation

A broad range of debilitating human diseases is connected with the failure of a specific protein to adopt or remain in its functional conformation and instead aggregate to insoluble deposits. These disorders (such as Alzheimer’s and Parkinson’s Diseases) impose enormous social and economic burden on society.

A major goal in attempts to understand protein misfolding diseases is to define the structures of protein species intermediate between correctly folded and aggregated, and extract a kinetic description of the aggregation process. This remains difficult, due to the inability of current approaches to analyse unstable protein complexes with structurally diverse populations, and consequently MS is ideally suited to this application. We use innovative MS methods to probe the aggregation pathway of disease related proteins and importantly, also investigate the structural basis of inhibitors of the aggregation process in order to identify new approaches for therapeutic intervention. The research also includes a focus on critical protein-chaperone and protein-lipid interactions, to provide unprecedented detail on the role of these assemblies in protein folding, and in particular formation of toxic species implicated in Alzheimer's and Parkinson’s Diseases.

 

Analysis of Unusual DNA Structures

Many variations from the well-known duplex DNA structure play key roles in a range of cellular processes.  These structures, such as triplex DNA shown at right, are often formed by repetitive DNA stretches (such as tri-nucleotide repeats) that are genetically unstable, and are associated with numerous hereditary neurological diseases that include muscular dystrophy, Friedreich’s ataxia and Huntington’s disease.  MS in combination with computational modelling offers a unique approach to studying the formation, structural properties and binding interactions of DNA triplex structures.  Aims of this research are to develop MS methodology to probe formation and structural properties of DNA triplexes associated with Friedrich’s ataxia and ligand binding interactions. Based on this research we expect to explore new leads for disruption of DNA triplex structures for treatment of Friedrich’s ataxia and related diseases.  We also hope to utilise the knowledge gained in understanding these structures to develop selective triplex forming molecules to modulate gene regulation in areas of gene technology.