Aggregation mechanism of polyglutamine diseases revealed using quantum chemical calculations, fragment molecular orbital calculations, molecular dynamics simulations, and binding free energy calculations

Polyglutamine (polyQ) diseases, including Huntington's disease (HD), are caused by expansion of polyQ-encoding repeats within otherwise unrelated gene products. The aggregation mechanism of polyQ diseases, the inhibition mechanism of Congo red, and the alleviation mechanism of trehalose were proposed here based on quantum chemical calculations and molecular dynamics simulations. The calculations and simulations revealed the following. The effective molecular bonding is between glutantine (Gln) and Gln (Gln + Gln), between Gin and Congo red (Gin + Congo red), and between Gin and trehalose (Gin + trehalose). The bonding strength is - 13.1 kcal/ mol for Gin + Gin, -24.4 kcal/mol for Gin + Congo red, and - 12.0 kcal/mol for Gin + trehalose. In the polyQ region, both the number of intermolecular Gin + Gin formations and the total calories generated by the Gin + Gin formation are proportional to the number of repetitions of Gin. We propose an aggregation mechanism whose heat generated by the intermolecular Gin + Gin formation causes the pathogeny of polyQ disease. In our aggregation mechanism, this generated heat collapses the host protein and promotes fibrillogenesis. Without contradiction, our mechanism can explain all the experimental results reported to date. Our mechanism can also explain the inhibition mechanism by Congo red as an inhibitor of polyglutamine-induced protein aggregation and the alleviation mechanism by trehalose as an alleviator of that aggregation. The inhibition mechanism by Congo red is explained by the strong interaction with Gin and by the characteristic structure of Congo red. (c) 2006 Elsevier B.V. All rights reserved.