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

The amyloid peptide congener A beta (10-35)-NH2 is simulated in an aqueous environment in both the wild type (Wr) and E22Q "Dutch" mutant forms. The o rigin of the noted increase in deposition activity resulting from the Dutch mutation is investigated. Multiple nanosecond time scale molecular dynamic s trajectories were performed and analyzed using a variety of measures of t he peptide's average structure, hydration, conformational fluctuations, and dynamics. The results of the study support the conclusions that 1) the E22 Q mutant and WT peptide are both stable in "collapsed coil" conformations c onsistent with the WT structure of Zhang et al. (2000, J. Struct. Biol. 130 :130-141); 2) the E22Q peptide is more flexible in solution, supporting ear ly claims that its equilibrium structural fluctuations are larger than thos e of the WT peptide; and 3) the local E22Q mutation leads to a change in th e first solvation layer in the region of the peptide's "hydrophobic patch," resulting in a more hydrophobic solvation of the mutant peptide. The simul ation results support the view that the noted increase in activity due to t he Dutch mutation results from an enhancement of the desolvation process th at is an essential step in the aggregation of the peptide.