Sammanfattning

Small soluble oligomers, and dimers in particular, of the amyloid beta-peptide (A beta) are believed to play an important pathological role in Alzheimer's disease. Here, we investigate the spontaneous dimerization of A beta 42, with 42 residues, by implicit solvent all-atom Monte Carlo simulations, for the wild-type peptide and the mutants F20E, E22G and E22G/I31E. The observed dimers of these variants share many overall conformational characteristics but differ in several aspects at a detailed level. In all four cases, the most common type of secondary structure is intramolecular antiparallel beta-sheets. Parallel, in-register beta-sheet structure, as in models for A beta fibrils, is rare. The primary force driving the formation of dimers is hydrophobic attraction. The conformational differences that we do see involve turns centered in the 20-30 region. The probability of finding turns centered in the 25-30 region, where there is a loop in A beta fibrils, is found to increase upon dimerization and to correlate with experimentally measured rates of fibril formation for the different A beta 42 variants. Our findings hint at reorganization of this part of the molecule as a potentially critical step in A beta aggregation. (C) 2011 Elsevier Ltd. All rights reserved.

Nyckelord

amyloid; protein aggregation; oligomerization; molecular simulation; all atom

Publicerad i

Journal of Molecular Biology
2011, Volym: 410, nummer: 2, sidor: 357-367
Utgivare: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD

SLU författare

• Härd, Torleif

  • Institutionen för molekylärbiologi, Sveriges lantbruksuniversitet
    

UKÄ forskningsämne

Biofysik
Biokemi och molekylärbiologi


Publikationens identifierare

DOI: https://doi.org/10.1016/j.jmb.2011.05.014

Permanent länk till denna sida (URI)

https://res.slu.se/id/publ/40819