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. 2021 Jul;89(7):762-780.
doi: 10.1002/prot.26057. Epub 2021 Feb 18.

β-sheet breakers with consecutive phenylalanines: Insights into mechanism of dissolution of β-amyloid fibrils

Adam Jarmuła  1 , Jan Ludwiczak  1   2 , Dariusz Stępkowski  3
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β-sheet breakers with consecutive phenylalanines: Insights into mechanism of dissolution of β-amyloid fibrils

Adam Jarmuła et al. Proteins. 2021 Jul.

Abstract

β-sheet breakers (BSB) constitute a class of peptide inhibitors of amyloidogenesis, a process which is a hallmark of many diseases called amyloidoses, including Alzheimer's disease (AD); however, the molecular details of their action are still not fully understood. Here we describe the results of the computational investigation of the three BSBs, iaβ6 (LPFFFD), iaβ5 (LPFFD), and iaβ6_Gly (LPFGFD), in complex with the fibril model of Aβ42 and propose the kinetically probable mechanism of their action. The mechanism involves the binding of BSB to the central hydrophobic core (CHC) region (LVFFA) of Aβ fibril and the π-stacking of its Phe rings both internally and with the Aβ fibril. In the process, the Aβ fibril undergoes distortion accumulating on the side of chain A (located on the odd tip of the fibril). In a single replica of extended molecular dynamics run of one of the iaβ6 poses, the distortion concludes in a dissociation of chain A from the fibril model of Aβ42. Altogether, we postulate that including consecutive Phe residues into BSBs docked around Phe 20 in the CHC region of Aβ42 improve their potency for dissolution of fibrils.

Keywords: amyloidogenesis; fibrils dissolution; molecular docking; molecular dynamics; peptide inhibitors.

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REFERENCES

    1. McDade E, Bateman RJ. Stop Alzheimer's before it starts. Nature. 2017;547(7662):153-155. https://doi.org/10.1038/547153a.
    1. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15(2):73-88. https://doi.org/10.1038/s41582-018-0116-6.
    1. Golde TE, DeKosky ST, Galasko D. Alzheimer's disease: the right drug, the right time. Science. 2018;362(6420):1250-1251. https://doi.org/10.1126/science.aau0437.
    1. Morley JE, Farr SA. The role of amyloid-beta in the regulation of memory. Biochem Pharmacol. 2014;88:479-485. https://doi.org/10.1016/j.bcp.2013.12.018.
    1. Yu Y, Jans DC, Winblad B, Tjernberg LO, Schedin-Weiss S. Neuronal Aβ42 is enriched in small vesicles at the presynaptic side of synapses. Life Sci Alliance. 2018;1(3):e201800028. https://doi.org/10.26508/lsa.201800028.

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