Stability of b sheet polyglutamine repeats in neurodegenerative diseases

Georgios Zamanakos, Nagarajan Vaidehi, Brian Palmer, Joyce Peng and William Goddard III

Materials and Process Simulation Center , CALTECH.

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Parsa Kazemi, Department of Biology, Caltech.

Several neurodegenerative diseases including Huntington's disease and Alzheimer's disease, have been found to be strongly associated with proteins containing a polyglutamine stretch which is greatly expanded from approximately 20 glutamines in normal individuals to more than 40 in affected individuals. The proteins with longer polyglutamine repeats lead to amyloid fibril formation which results in cell degradation. The amyloids are ordered and stable aggregates and are made up of b sheet structures as the nucleus. If these aggregates are the primary cause of polyglutamine-expansion disorders, one of the therapeutic strategies might be to prevent the mutant proteins from forming aggregates.

In this study we have focussed in understanding the stability of b sheet as a function of all 20 amino acid substitutions. We have performed both random and systematic levels and types of substitution. The idea is to find out which combination of amino acid substitution would maximize the disruption of b sheet structure in longer glutamine repeats. We have used MPSim with NEIMO/SGB solvation in these studies. This study should suggest possible mutation candidates for experimental study in animal models. This study would be extremely useful to the neurobiologists working on the pathogenesis of neurodegenerative diseases, which is in the heart of research in neurobiology.