We report a strategy for realizing tunable electrical conductivity in metal-organic frameworks (MOFs) in which the nanopores are infiltrated with redox-active, conjugated guest molecules. This approach is demonstrated using thin-film devices of the MOF Cu3(BTC)2 (also known as HKUST-1; BTC, benzene-1,3,5-tricarboxylic acid) infiltrated with the molecule 7,7,8,8-tetracyanoquinododimethane (TCNQ). Tunable, air-stable electrical conductivity over six orders of magnitude is achieved, with values as high as 7 siemens per meter. Spectroscopic data and first-principles modeling suggest that the conductivity arises from TCNQ guest molecules bridging the binuclear copper paddlewheels in the framework, leading to strong electronic coupling between the dimeric Cu subunits. These ohmically conducting porous MOFs could have applications in conformal electronic devices, reconfigurable electronics, and sensors.

Copper is implicated in the in vitro formation and toxicity of Alzheimer's disease amyloid plaques containing the beta-amyloid (Abeta) peptide (Bush, A. I., et al. (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 11934). By low temperature electron paramagnetic resonance (EPR) spectroscopy, the importance of the N-terminus in creating the Cu(2+) binding site in native Abeta has been examined. Peptides that contain the proposed binding site for Cu(2+)-three histidines (H6, H13, and H14) and a tyrosine (Y10)-but lack one to three N-terminal amino acids, do not bind Cu(2+) in the same coordination environment as the native peptide. EPR spectra of soluble Abeta with stoichiometric amounts of Cu(2+) show type 2 Cu(2+) EPR spectra for all peptides. The ligand donor atoms to Cu(2+) are 3N1O when Cu(2+) is bound to any of the Abetapeptides (Abeta16, Abeta28, Abeta40, and Abeta42) that contain the first 16 amino acids of full-length Abeta. When a Y10F mutant of Abeta is used, the coordination environment for Cu(2+) remains 3N1O and Cu(2+) EPR spectra of this mutant are identical to the wild-type spectra. Isotopic labeling experiments show that water is not the O-atom donor to Cu(2+) in Abeta fibrils or in the Y10F mutant. Further, we find that Cu(2+) cannot be removed from Cu(2+)-containing fibrils by washing with buffer, but that Cu(2+) binds to fibrils initially assembled without Cu(2+) in the same coordination environment as in fibrils assembled with Cu(2+). Together, these results indicate (1) that the O-atom donor ligand to Cu(2+) in Abeta is not tyrosine, (2) that the native Cu(2+) binding site in Abeta is sensitive to small changes at the N-terminus, and (3) that Cu(2+) binds to Abetafibrils in a manner that permits exchange of Cu(2+) into and out of the fibrillar architecture.

Oxidative stress has been suggested to contribute to neuronal apoptosis associated with Alzheimer's disease (AD). Copper may participate in oxidative stress through redox-cycling between its +2 and +1 oxidation states to generate reactive oxygen species (ROS). In vitro, copper binds to the amyloid-β peptide of AD and in vivo, copper is associated with amyloid plaques characteristic of AD. As a result, the AβCuI complex may be a critical reactant involved in ROS associated with AD etiology. To characterize the AβCuI complex, we have pursued X-ray absorption (XAS) and EPR spectroscopy of AβCuII and AβCuI (produced by ascorbate reduction of AβCuII). The AβCuII complex Cu K-edge X-ray absorption spectrum is indicative of a square-planar CuII center with mixed N/O ligation. Multiple scattering analysis of the extended X-ray absorption fine structure (EXAFS) data for AβCuII indicate that two of the ligands are imidazole groups of histidine ligands, indicating a (NIm)2(N/O)2 CuII ligation sphere for AβCuII. After reduction of the AβCuII complex with ascorbate, the edge region decreases by ∼4 eV in energy. The X-ray absorption near-edge spectrum (XANES) region of AβCuI displays an intense pre-edge feature at 8984.1(2) eV. EXAFS data fitting yielded a two coordinate geometry with two imidazole ligands coordinated to CuI at 1.877(2) Å in a linear geometry. Ascorbate reduction of AβCuII under inert atmosphere and subsequent air oxidation of AβCuI to regenerate AβCuII was monitored by low-temperature EPR spectroscopy. Slow re-appearance of the AβCuII EPR signal indicates that O2 oxidation of the AβCuI complex is kinetically sluggish, and Aβ damage is occurring following reoxidation of AβCuI by O2. Together, these results lead us to hypothesize that CuI is ligated by His13 and His14 in a linear coordination environment in Aβ, that Aβ may be playing a neuroprotective role, and that metal-mediated oxidative damage of Aβ occurs over multiple redox-cycles.

Amyloid-beta (Abeta) peptide is the principal constituent of plaques associated with Alzheimer's disease and is thought to be responsible for the neurotoxicity associated with the disease. Metal ions have been hypothesized to play a role in the formation and neurotoxicity of aggregates associated with Alzheimer's disease (Bush, A. I.; et al. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 11934). Elucidation of the chemistry through which transition-metal ions participate in the assembly and toxicity of Abeta oligomers is important to drug design efforts if inhibition of Abeta containing bound metal ions becomes a treatment for Alzheimer's disease. In this paper, we report electron paramagnetic resonance (EPR) spectroscopic characterization of Cu(2+) bound to soluble and fibrillar Abeta. Addition of stoichiometric amounts of Cu(2+) to soluble Abeta produces an EPR signal at 10 K with observable Cu(2+) hyperfine lines. A nearly identical spectrum is observed for Abetafibrils assembled in the presence of Cu(2+). The EPR parameters are consistent with a Type 2 Cu(2+) center with three nitrogen donor atoms and one oxygen donor atom in the coordination sphere of Cu(2+): g( parallel) = 2.26 and A( parallel) = 174 +/- 4 G for soluble Abeta with Cu(2+), and g( parallel) = 2.26 and A( parallel) = 175 +/- 1 G for Abeta fibrils assembled with Cu(2+). Investigation of the temperature dependence of the EPR signal for Cu(2+) bound to soluble Abetaor Cu(2+) in fibrillar Abeta shows that the Cu(2+) center displays normal Curie behavior, indicating that the site is a mononuclear Cu(2+) site. Fibrils assembled in the presence of Cu(2+) contain one Cu(2+) ion per peptide. These results show that the ligand donor atom set to Cu(2+) does not change during organization of Abetamonomers into fibrils and that neither soluble nor fibrillar forms of Abeta(1-40) with Cu(2+) contain antiferromagnetically exchange-coupled binuclear Cu(2+) sites in which two Cu(2+) ions are bridged by an intervening ligand.

Copper has been proposed to play a role in Alzheimer's disease through interactions with the amyoid-beta (Abeta) peptide. The coordination environment of bound copper as a function of Cu:Abeta stoichiometry and Abeta oligomerization state are particularly contentious. Using low-temperature electron paramagnetic resonance (EPR) spectroscopy, we spectroscopically distinguish two Cu(II) binding sites on both soluble and fibrillar Abeta (for site 1, A parallel = 168 +/- 1 G and g parallel = 2.268; for site 2, A parallel = 157 +/- 2 G and g parallel = 2.303). When fibrils that have been incubated with more than 1 equiv of Cu(II) are washed, the second Cu(II) ion is removed, indicating that it is only weakly bound to the fibrils. No change in the Cu(II) coordination environment is detected by EPR spectroscopy of Cu(II) with Abeta (1:1 ratio) collected as a function of Abeta fibrillization time, which indicates that the Cu(II) environment is independent of Abeta oligomeric state. The initial Cu(II)-Abeta complexes go on to form Cu(II)-containing Abeta fibrils. Transmission electron microscopy images of Abeta fibrils before and after Cu(II) addition are the same, showing that once incorporated, Cu(II) does not affect fibrillar structure; however, the presence of Cu(II) appears to induce fibril-fibril association. On the basis of our results, we propose a model for Cu(II) binding to Abeta during fibrillization that is independent of peptide oligomeric state.

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Alzheimer's disease (AD) is the leading cause of dementia in the elderly, affecting almost 15 million people. 1 A defining feature of AD is the post-mortem observation of extracellular proteinaceous plaques composed predominantly of the amyloid-beta (Aβ) peptide. In addition to Aβ, the redox-active metal ions iron and copper are found in AD plaques, 2,3 suggesting that these metal ions are involved in AD etiology. 4 Copper is particularly significant because it is implicated in other amyloidosis 5 and its misregulation results in neuropathology associated with Menkes and Wilson's diseases. 6

Guanine quadruplexes (GQ) are four‐stranded DNA structures formed by guanine‐rich DNA sequences. The formation of GQs inhibits cancer cell growth, although the detection of GQs in vivo has proven difficult, in part because of their structural diversity. The development of GQ‐selective fluorescent reporters would enhance our ability to quantify the number and location of GQs, ultimately advancing biological studies of quadruplex relevance and function. N‐methylmesoporphyrin IX (NMM) interacts selectively with parallel‐stranded GQs; in addition, its fluorescence is sensitive to the presence of DNA, making this ligand a possible candidate for a quadruplex probe. In the present study, we investigated the effect of DNA secondary structure on NMM fluorescence. We found that NMM fluorescence increases by about 60‐fold in the presence of parallel‐stranded GQs and by about 40‐fold in the presence of hybrid GQs. Antiparallel GQs lead to lower than 10‐fold increases in NMM fluorescence. Single‐stranded DNA, duplex, or i‐motif, induce no change in NMM fluorescence. We conclude that NMM shows promise as a ‘turn‐on’ fluorescent probe for detecting quadruplex structures, as well as for differentiating them on the basis of strand orientation.