Aromaticity and amyloid formation: Effect of π-electron distribution and aryl substituent geometry on the self-assembly of peptides derived from hIAPP22–29

• Published in: Archives of biochemistry and biophysics Vol. 567; pp. 46 - 58
• Main Authors: Profit, Adam A., Vedad, Jayson, Saleh, Mohamad, Desamero, Ruel Z.B.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.02.2015
• Subjects: Aggregation; Amyloid formation; Raman spectroscopy; Thioflavin T fluorescence; β-Sheet; π-Stacking; Aggregation; π-Stacking; Amyloid formation; Raman spectroscopy; Thioflavin T fluorescence; β-Sheet
• DOI: 10.1016/j.abb.2014.12.008
• ISSN: 0003-9861

[Display omitted] •hIAPP22–29 peptides with electron poor aromatic systems readily aggregate.•hIAPP22–29 peptides with electron rich aromatic systems do not aggregate.•The steric and electronic effects of aryl substituents have been deconvoluted.•Electron rich hIAPP22–29 peptides inhibit amyloid formation by full-length amylin.•A mechanism for the inhibition of amylin by hIAPP22–29 peptides is proposed. A comprehensive investigation of peptides derived from the 22–29 region of human islet amyloid polypeptide (hIAPP) that contain phenylalanine analogs at position 23 with a variety of electron donating and withdrawing groups, along with heteroaromatic surrogates, has been employed to interrogate how π-electron distribution effects amyloid formation. Kinetic aggregation studies using turbidity measurements indicate that electron rich aromatic ring systems consistently abolish the amyloidogenic propensity of hIAPP22–29. Electron poor systems modulate the rate of aggregation. Raman and Fourier transform infrared spectroscopy confirm the parallel β-sheet secondary structure of aggregates derived from peptides containing electron poor phenylalanine analogs and provide direct evidence of ring stacking. Transmission electron microscopy confirms the presence of amyloid fibrils. The effect of aryl substituent geometry on peptide self-assembly reveals that the electronic nature of substituents and not their steric profile is responsible for failure of the electron donating group peptides to aggregate. Non-aggregating hIAPP22–29 peptides were found to inhibit the self-assembly of full-length hIAPP1–37. The most potent inhibitory peptides contain phenylalanine with the p-amino and p-formamido functionalities. These novel peptides may serve as leads for the development of future aggregation inhibitors. A potential mechanism for inhibition of amylin self-assembly by electron rich hIAPP22–29 peptides is proposed.