Mechanism for the α-helix to β-hairpin transition

被引:240
作者
Ding, F
Borreguero, JM
Buldyrey, SV
Stanley, HE
Dokholyan, NV
机构
[1] Boston Univ, Dept Phys, Ctr Polymer Studies, Boston, MA 02215 USA
[2] Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA
关键词
hydrogen bond; amyloid fibril; aggregation; entropy; molecular dynamics;
D O I
10.1002/prot.10468
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The aggregation of alpha-helix-rich proteins into beta-sheet-rich amyloid fibrils is Associated with fatal diseases, such as Alzheimer's disease and prion disease. During an aggregation process, protein secondary structure elements-alpha-helices-undergo conformational changes to beta-sheets. The fact that proteins With different sequences and structures undergo a similar transition on aggregation suggests that the sequence nonspecific hydrogen bond interaction among protein backbones is an important factor. We perform molecular dynamics simulations of a polyalanine model, which is an alpha-helix in its native state and observe a metastable beta-hairpin intermediate. Although a beta-hairpin has larger potential energy than an alpha-helix, the entropy of a beta-hairpin is larger because of fewer constraints imposed by the hydrogen bonds. In the vicinity of the transition temperature, We observe the interconversion of the alpha-helix and beta-sheet states via a random coil state. We also study the effect of the environment by varying the relative strength of side-chain interactions for a designed peptide-an alpha-helix in its native state. For a certain range of side-chain interaction strengths, we find that the intermediate beta-hairpin state is destabilized and even disappears, suggesting an important role of the environment in the aggregation propensity of a peptide. (C) 2003 Wiley-Liss, Inc.
引用
收藏
页码:220 / 228
页数:9
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