Solvent and mutation effects on the nucleation of amyloid β-protein folding

被引:105
作者
Cruz, L [1 ]
Urbanc, B
Borreguero, JM
Lazo, ND
Teplow, DB
Stanley, HE
机构
[1] Boston Univ, Ctr Polymer Sci, Boston, MA 02215 USA
[2] Boston Univ, Dept Phys, Boston, MA 02215 USA
[3] SUNY Buffalo, Ctr Excellence Bioinformat, Buffalo, NY 14203 USA
[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA
关键词
molecular dynamics; Alzheimer's disease; hydrophobic interactions; salt bridges;
D O I
10.1073/pnas.0509276102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Experimental evidence suggests that the folding and aggregation of the amyloid beta-protein (A beta) into oligomers is a key pathogenetic event in Alzheimer's disease. Inhibiting the pathologic folding and oligomerization of A beta could be effective in the prevention and treatment of Alzheimer's disease. Here, using all-atom molecular dynamics simulations in explicit solvent, we probe the initial stages of folding of a decapeptide segment of A beta, A beta(21-30), shown experimentally to nucleate the folding process. In addition, we examine the folding of a homologous decapeptide containing an amino acid substitution linked to hereditary cerebral hemorrhage with amyloidosis-Dutch type, [Gln-22]A beta(21-30). We find that: (i) when the decapeptide is in water, hydrophobic interactions and transient salt bridges between Lys-28 and either Glu-22 or Asp-23 are important in the formation of a loop in the Val-24-Lys-28 region of the wild-type decapeptide; (h) in the presence of salt ions, salt bridges play a more prominent role in the stabilization of the loop; (iii) in water with a reduced density, the decapeptide forms a helix, indicating the sensitivity of folding to different aqueous environments; and (iv) the "Dutch" peptide in water, in contrast to the wild-type peptide, fails to form a long-lived Val-24-Lys-28 loop, suggesting that loop stability is a critical factor in determining whether A beta folds into pathologic structures.
引用
收藏
页码:18258 / 18263
页数:6
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