The stability of monomeric intermediates controls amyloid formation: Aβ25-35 and its N27Q mutant

Abstract

The structure and stabilities of the intermediates affect protein folding as well as misfolding and amyloid formation. By applying Kramer's theory of barrier crossing and a Morse-function-like energy landscape, we show that intermediates with medium stability dramatically increase the rate of amyloid formation; on the other hand, very stable and very unstable intermediates sharply decrease amyloid formation. Remarkably, extensive molecular dynamics simulations and conformational energy landscape analysis of Aβ25-35 and its N27Q mutant corroborate the mathematical description. Both experimental and current simulation results indicate that the core of the amyloid structure of Aβ25-35 formed from residues 28-35. A single mutation of N27Q of Aβ25-35 makes the Aβ25-35 N27Q amyloid-free. Energy landscape calculations show that Aβ25-35 has extended intermediates with medium stability that are prone to form amyloids, whereas the extended intermediates for Aβ25-35 N27Q split into stable and very unstable species that are not disposed to form amyloids. The results explain the contribution of both α-helical and β-strand intermediates to amyloid formation. The results also indicate that the structure and stability of the intermediates, as well as of the native folded and the amyloid states can be targeted in drug design. One conceivable approach is to stabilize the intermediates to deter amyloid formation. © 2006 by the Biophysical Society.