TY - JOUR
T1 - The stability of monomeric intermediates controls amyloid formation
T2 - Aβ25-35 and its N27Q mutant
AU - Ma, Buyong
AU - Nussinov, Ruth
N1 - Funding Information:
This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number NO1-CO-12400, and by the United States Army Medical Research Acquisition Activity under grant W81XWH-05-1-0002. The research of R. Nussinov in Israel was supported in part by the Center of Excellence in Geometric Computing and its Applications, funded by the Israel Science Foundation (administered by the Israel Academy of Sciences). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.
PY - 2006/5
Y1 - 2006/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33646192684&partnerID=8YFLogxK
U2 - 10.1529/biophysj.105.075309
DO - 10.1529/biophysj.105.075309
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AN - SCOPUS:33646192684
SN - 0006-3495
VL - 90
SP - 3365
EP - 3374
JO - Biophysical Journal
JF - Biophysical Journal
IS - 10
ER -