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Structure of the 21–30 fragment of amyloid -protein

¹ Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, California 93106, USA
² Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA

(RECEIVED January 4, 2006; FINAL REVISION February 28, 2006; ACCEPTED March 6, 2006)

Folding and self-assembly of the 42-residue amyloid -protein (A) are linked to Alzheimer's disease (AD). The 21–30 region of A, A(21–30), is resistant to proteolysis and is believed to nucleate the folding of full-length A. The conformational space accessible to the A(21–30) peptide is investigated by using replica exchange molecular dynamics simulations in explicit solvent. Conformations belonging to the global free energy minimum (the "native" state) from simulation are in good agreement with reported NMR structures. These conformations possess a bend motif spanning the central residues V24–K28. This bend is stabilized by a network of hydrogen bonds involving the side chain of residue D23 and the amide hydrogens of adjacent residues G25, S26, N27, and K28, as well as by a salt bridge formed between side chains of K28 and E22. The non-native states of this peptide are compact and retain a native-like bend topology. The persistence of structure in the denatured state may account for the resistance of this peptide to protease degradation and aggregation, even at elevated temperatures.

Keywords: Alzheimer A peptide; replica exchange molecular dynamics simulations; sampling of conformational space

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