Physical chemistry of polyglutamine: intriguing tales of a monotonous sequence.

Polyglutamine (polyQ) sequences of unknown normal function are present in a significant number of proteins, and their repeat expansion is associated with a number of genetic neurodegenerative diseases. PolyQ solution structure and properties are important not only because of the normal and abnormal biology associated with these sequences but also because they represent an interesting case of a biologically relevant homopolymer. As the common thread in expanded polyQ repeat diseases, it is important to understand the structure and properties of simple polyQ sequences. At the same time, experience has shown that sequences attached to polyQ, whether in artificial constructs or in disease proteins, can influence structure and properties. The two major contenders for the molecular source of the neurotoxicity implicit in polyQ expansion within disease proteins are a populated toxic conformation in the monomer ensemble and a toxic aggregated species. This review summarizes experimental and computational studies on the solution structure and aggregation properties of both simple and complex polyQ sequences, and their repeat-length dependence. As a representative of complex polyQ proteins, the behavior of huntingtin N-terminal fragments, such as exon-1, receives special attention.