Amyloid β-protein monomer structure:: A computational and experimental study

被引:223
|
作者
Baumketner, A
Bernstein, SL
Wyttenbach, T
Bitan, G
Teplow, DB
Bowers, MT [1 ]
Shea, JE
机构
[1] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA
[2] Univ Calif Los Angeles, David Geffin Sch Med, Dept Neurol, Los Angeles, CA 90095 USA
关键词
structure; mass spectrometry; correlation of structure with spectra and other properties; new methods; computational analysis of protein structure; molecular dynamics;
D O I
10.1110/ps.051762406
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 structural properties of the A beta 42 peptide, a main constituent of the amyloid plaques formed in Alzheimer's disease, were investigated through a combination of ion-mobility mass spectrometry and theoretical modeling. Replica exchange molecular dynamics simulations using a fully atomic description of the peptide and implicit water solvent were performed on the -3 charge state of the peptide, its preferred state under experimental conditions. Equilibrated structures at 300 K were clustered into three distinct families with similar structural features within a family and with significant root mean square deviations between families. An analysis of secondary structure indicates the A beta 42 peptide conformations are dominated by loops and turns but show some helical structure in the C-terminal hydrophobic tail. A second calculation on A beta 42 in a solvent-free environment yields compact structures turned "inside out" from the solution structures (hydrophobic parts on the outside, polar parts on the inside). Ion mobility experiments on the A beta 42-3 charge state electrosprayed from solution yield a bimodal arrival time distribution. This distribution can be quantitatively fit using cross-sections from dehydrated forms of the three families of calculated solution structures and the calculated solvent-free family of structures. Implications of the calculations on the early stages of aggregation of A beta 42 are discussed.
引用
收藏
页码:420 / 428
页数:9
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