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New Insights into the Mechanism of Alzheimer Amyloid-β Fibrillogenesis Inhibition by N-Methylated Peptides

Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106

Correspondence: Address reprint requests to Joan-Emma Shea, E-mail: shea{at}chem.ucsb.edu.

Alzheimer's disease is a debilitating neurodegenerative disorder associated with the abnormal self-assembly of amyloid-β (Aβ) peptides into fibrillar species. N-methylated peptides homologous to the central hydrophobic core of the Aβ peptide are potent inhibitors of this aggregation process. In this work, we use fully atomistic molecular dynamics simulations to study the interactions of the N-methylated peptide inhibitor Aβ16–20m (Ac-Lys¹⁶-(Me)Leu¹⁷-Val¹⁸-(Me)Phe¹⁹-Phe²⁰-NH₂) with a model protofilament consisting of Alzheimer Aβ16–22 peptides. Our simulations indicate that the inhibitor peptide can bind to the protofilament at four different sites: 1), at the edge of the protofilament; 2), on the exposed face of a protofilament layer; 3), between the protofilament layers; and 4), between the protofilament strands. The different binding scenarios suggest several mechanisms of fibrillogenesis inhibition: 1), fibril inhibition of longitudinal growth (in the direction of monomer deposition); 2), fibril inhibition of lateral growth (in the direction of protofilament assembly); and 3), fibril disassembly by strand removal and perturbation of the periodicity of the protofilament (disruption of fibril morphology). Our simulations suggest that the Aβ16-20m inhibitor can act on both prefibrillar species and mature fibers and that the specific mechanism of inhibition may depend on the structural nature of the Aβ aggregate. Disassembly of the fibril can be explained by a mechanism through which the inhibitor peptides bind to disaggregated or otherwise free Aβ16–22 peptides in solution, leading to a shift in the equilibrium from a fibrillar state to one dominated by inhibitor-bound Aβ16–22 peptides.

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