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Biophys. J. BioFAST: First Published February 24, 2006. doi:10.1529/biophysj.105.075309
© 2006 by the Biophysical Society.

A more recent version of this article appeared on May 15, 2006.
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BIOPHYSICAL THEORY AND MODELING

The Stability of Monomeric Intermediates Controls Amyloid Formation: A{beta}25-35 and its N27Q Mutant

Buyong Ma 1 and Ruth Nussinov 2*

1 NCI-frederick, NIH
2 SAIC Frederick, Inc

* To whom correspondence should be addressed. E-mail: ruthn{at}ncifcrf.gov.

Submitted on September 29, 2005
Revised on November 19, 2005
Accepted on 10 January 2006


  Abstract
The structure and stabilities of the intermediates affect protein folding as well as misfolding and amyloid formation. By applying Kramers 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 A{beta}25-35 and its N27Q mutant corroborate the mathematical description. Both experimental and current simulation results indicate that the core of the amyloid structure of A{beta}25-35 formed from residues 28-35. A single mutation of N27Q of A{beta}25-35 makes the A{beta}25-35 N27Q amyloid free. Energy landscape calculations show that A{beta}25-35 has extended intermediates with medium stability, which are prone to form amyloids, while the stability of extended intermediates for A{beta}25-35 N27Q split into stable and very unstable species that are not disposed to form amyloids. The results explain the contribution of both {alpha}-helical as well as {beta}-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.

Key Words: A-beta peptide, Amyloid, Misfolding, energy landscape, intermediate, misfolding




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Copyright © 2006 by the Biophysical Society.