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J Phys Chem B. 2016 Jul 7;120(26):5874-83. doi: 10.1021/acs.jpcb.6b00830. Epub 2016 Apr 1.

Aggregation of Chameleon Peptides: Implications of α-Helicity in Fibril Formation.

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  • 1Department of Neurology, David Geffen School of Medicine at UCLA, Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.

Abstract

We investigate the relationship between the inherent secondary structure and aggregation propensity of peptides containing chameleon sequences (i.e., sequences that can adopt either α or β structure depending on context) using a combination of replica exchange molecular dynamics simulations, ion-mobility mass spectrometry, circular dichroism, and transmission electron microscopy. We focus on an eight-residue long chameleon sequence that can adopt an α-helical structure in the context of the iron-binding protein from Bacillus anthracis (PDB id 1JIG ) and a β-strand in the context of the baculovirus P35 protein (PDB id 1P35 ). We show that the isolated chameleon sequence is intrinsically disordered, interconverting between α-helical and β-rich conformations. The inherent conformational plasticity of the sequence can be constrained by addition of flanking residues with a given secondary structure propensity. Intriguingly, we show that the chameleon sequence with helical flanking residues aggregates rapidly into fibrils, whereas the chameleon sequence with flanking residues that favor β-conformations has weak aggregation propensity. This work sheds new insights into the possible role of α-helical intermediates in fibril formation.

PMID:
27001160
PMCID:
PMC4936924
[Available on 2017-07-07]
DOI:
10.1021/acs.jpcb.6b00830
[PubMed - in process]
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