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1 Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
2 Department of Chemistry and Biochemistry and the Institute for Physical Science and Technology, University of Maryland, College Park, Maryland 20472, USA
Reprint requests to: John E. Straub, Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA; e-mail: straub{at}bu.edu; fax: (617) 353-6466.
The activity of the Alzheimer's amyloid ß-peptide is a sensitive function of the peptide's sequence. Increased fibril elongation rate of the E22Q Dutch mutant of the Alzheimer's amyloid ß-peptide relative to that of the wild-type peptide has been observed. The increased activity has been attributed to a larger propensity for the formation of ß structure in the monomeric E22Q mutant peptide in solution relative to the WT peptide. That hypothesis is tested using four nanosecond timescale simulations of the WT and Dutch mutant forms of the Aß(10–35)-peptide in aqueous solution. The simulation results indicate that the propensity for formation of ß-structure is no greater in the E22Q mutant peptide than in the WT peptide. A significant measure of "flickering" of helical structure in the central hydrophobic cluster region of both the WT and mutant peptides is observed. The simulation results argue against the hypothesis that the Dutch mutation leads to a higher probability of formation of ß-structure in the monomeric peptide in aqueous solution. We propose that the greater stability of the solvated WT peptide relative to the E22Q mutant peptide leads to decreased fibril elongation rate in the former. Stability difference is due to the differing charge state of the two peptides. The other proposal leads to the prediction that the fibril elongation rates for the WT and the mutant E22Q should be similar under acid conditions.
Keywords: Aß-peptide; amyloid; molecular dynamics simulation; amyloidosis; aggregation; E22Q Dutch mutant peptide; conformational analysis; hydration
Abbreviations: Aß, ß-amyloid peptide • WT, wild type • CD, circular dichroism spectroscopy • FTIR, Fourier transform infrared spectroscopy • NMR, nuclear magnetic resonance spectroscopy • NOE, nuclear Overhauser enhancement spectroscopy • MD, molecular dynamics • URMS, unit vector root mean square difference
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