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Probing the origins of increased activity of the E22Q "Dutch" mutant Alzheimer's beta-amyloid peptide

Probing the origins of increased activity of the E22Q "Dutch" mutant Alzheimer's beta-amyloid peptide

Biophysical Journal 81(2): 697-709

The amyloid peptide congener A beta(10--35)-NH(2) is simulated in an aqueous environment in both the wild type (WT) and E22Q "Dutch" mutant forms. The origin of the noted increase in deposition activity resulting from the Dutch mutation is investigated. Multiple nanosecond time scale molecular dynamics trajectories were performed and analyzed using a variety of measures of the peptide's average structure, hydration, conformational fluctuations, and dynamics. The results of the study support the conclusions that 1) the E22Q mutant and WT peptide are both stable in "collapsed coil" conformations consistent with the WT structure of, J. Struct. Biol. 130:130--141); 2) the E22Q peptide is more flexible in solution, supporting early claims that its equilibrium structural fluctuations are larger than those of the WT peptide; and 3) the local E22Q mutation leads to a change in the first solvation layer in the region of the peptide's "hydrophobic patch," resulting in a more hydrophobic solvation of the mutant peptide. The simulation results support the view that the noted increase in activity due to the Dutch mutation results from an enhancement of the desolvation process that is an essential step in the aggregation of the peptide.

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Accession: 047080021

Download citation: RISBibTeXText

PMID: 11463618

DOI: 10.1016/s0006-3495(01)75734-7

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