A Mobile Precursor Determines Amyloid-β Peptide Fibril Formation at Interfaces

Lei Shen , Takuji Adachi , David Vanden Bout , and X.-Y. Zhu * Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, United States J. Am. Chem. Soc., Article ASAP DOI: 10.1021/ja305398f Publication Date (Web): August 6, 2012 Copyright © 2012 American Chemical Society zhu@cm.utexas.edu

 The aggregation of peptides into amyloid fibrils plays a crucial role in various neurodegenerative diseases. While it has been generally recognized that fibril formation in vivo may be greatly assisted or accelerated by molecular surfaces, such as cell membranes, little is known about the mechanism of surface-mediated fibrillation. Here we study the role of adsorbed Alzheimer’s amyloid-β peptide (Aβ42) on surface-mediated fibrillation using polymer coatings of varying hydrophobicity as well a supported lipid bilayer membrane. Using single molecule fluorescent tracking and atomic force microscopy imaging, we show that weakly adsorbed peptides with two-dimensional diffusivity are critical precursors to fibril growth on surfaces. This growth mechanism is inhibited on the highly hydrophilic surface where the surface coverage of adsorbed peptides is negligible or on the highly hydrophobic surface where the diffusion constant of the majority of adsorbed peptides is too low. Physical properties that favor weakly adsorbed peptides with sufficient translational mobility can locally concentrate peptide molecules on the surface and promote inter-peptide interaction via two-dimensional confinement, leading to fibrillation at Aβ peptide concentration many orders of magnitude below the critical concentration for fibrillation in the bulk solution.

A Mechano-Electronic DNA Switch

Jason M. Thomas †‡, Hua-Zhong Yu *‡, and Dipankar Sen *†‡

^‡Department of Chemistry and ^†Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6

J. Am. Chem. Soc., Article ASAP

DOI: 10.1021/ja303530y

Publication Date (Web): July 26, 2012

Copyright © 2012 American Chemical Society

sen@sfu.ca; hzyu@sfu.ca

We report a new kind of DNA nanomachine that, fueled by Hg²⁺ binding and sequestration, couples mechanical motion to the multiply reversible switching of through-DNA charge transport. This mechano-electronic DNA switch consists of a three-way helical junction, one arm of which is a T-T mismatch containing Hg²⁺-binding domain. We demonstrate, using chemical footprinting and by monitoring charge-flow-dependent guanine oxidation, that the formation of T-Hg²⁺-T base pairs in the Hg²⁺-binding domain sharply increases electron–hole transport between the other two Watson–Crick-paired stems, across the three-way junction. FRET measurements are then used to demonstrate that Hg²⁺ binding/dissociation, and the concomitant increase/decrease of hole transport efficiency, are strongly linked to specific mechanical movements of the two conductive helical stems. The increase in hole transport efficiency upon Hg²⁺ binding is tightly coupled to the movement of the conductive stems from a bent arrangement toward a more linear one, in which coaxial stacking is facilitated. This switch offers a paradigm wherein the performance of purely mechanical work by a nanodevice can be conveniently monitored by electronic measurement.

False-colored scanning electron microscopy image of innate immune cells and the parasite Trypanosoma brucei