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Chemical shifts.

The minimalists' transistor--a styrene molecule and a negative charge

While it is straightforward to make conductance or resistance measurements of bulk materials, it is understandably much more difficult to measure the conductance through an individual molecule--not least because the "electrodes" that need to be attached are typically much larger than the molecule under study. Those measurements are important, however, for a variety of fields--from conducting polymers to organic light-emitting diodes. Robert Wolkow and his co-workers Paul Piva, Janik Zikovsky, and Stanislav Dogel at the University of Alberta together with collaborators Gino DiLabio, MCIC, Jason Pitters, MCIC, and Moh'd Rezeq at the National Institute for Nanotechnology (Edmonton, AB) and Werner Hofer at the University of Liverpool, U.K., have reported such single molecule conductance measurements on styrene, and were further able to observe a dramatic change in conductivity depending on the presence of a nearby negative electric charge (Nature, 435 (2005) p. 658). The experiment makes elegant use of the ability of a scanning tunnelling microscope to image--with atomic resolution--the tunnelling current from the silicon substrate (one electrode) through the deposited styrene molecules (the conductor) to the STM tip (the other electrode). Contrary to popular belief, the STM does not "image atoms," but rather shows where on the surface there exist easy ways for electrons to tunnel to the STM tip, which is essentially a spatially resolved conductance measurement. The University of Alberta group uses a highly n-doped silicon substrate, then terminates most of the "dangling bonds" on the cleaved surface with hydrogen. Ultimately, this leaves a more or less featureless surface on which the few remaining dangling bonds light up as beacons, since they have acquired a negative charge. Upon exposure to styrene, the styrene molecules attach to the negative charge by electrostatic interactions, and to each other by [pi]--stacking interactions--thereby forming neat rows that would also light up under the STM tip if electrons were allowed to flow through them.

Now, when these rows of styrene molecules are imaged under low negative bias, not much is seen on the STM image other then the negatively charged dangling bond (see Figure 1). When, at the other extreme, the bias is very large, all styrene molecules happily help conduct electrons from the surface to the tip and the entire row lights up. At intermediate bias an interesting observation is made: the conductivity then depends on how close the styrene molecule is to the negative charge--the closest styrene molecules having a much higher conductivity compared to those near the end of the row. The sloping conductance effect is observable even at room temperature and indicates that the static electric field originating from the charge significantly increases the conductivity of nearby molecules. The observation has attracted considerable attention because this system contains all the basic ingredients of a single-molecule transistor--the charged dangling bond takes the function of the base, whereas the silicon substrate and the STM tip act as emitter and collector.

[FIGURE 1 OMITTED]

The researchers could furthermore make the sloping effect disappear completely when the dangling bond is reacted with TEMPO and reappear when TEMPO is removed. One can therefore consider the row of styrene molecules a chemically triggered single-molecule electrical sensor.

Modelling of the field-induced conductance increase was done by calculating the styrene molecular orbitals and their associated energy. The highest lying orbital is largely located on the styrene molecules closest to the negative charge and becomes the gateway to electron conduction when the sampling bias is small. When a larger bias is applied, all MO's contribute to the conductance and the imaged charge density appears evenly distributed along the row of styrene molecules.

Obedient solvents switch polarity on demand.

Imagine turning chloroform into dimethyl formamide with carbon dioxide as the only reagent, and then reversing the process with nitrogen gas. This is essentially what Philip Jessop, MCIC, Canada Research Chair in green chemistry at Queen's University, and graduate students David Heldebrant and Xiaowang Li, ACIC, have done. Their publication (Nature, 436 (2005) p. 1102), co-authored by collaborators Charles Eckert and Charles Liotta from the Georgia Institute of Technology, describes the equivalent of this reaction in which the polarity of a solvent is tuned from very non-polar to highly polar by the addition of gases. These so called "switchable" solvents have two main components, an amidine base such as DBU (1,8-diazabicyclo-[5.4.0]-undec-7-ene) and an alcohol such as hexanol. Upon exposure to one atmosphere of carbon dioxide, the mixture is converted into a carbonate salt (Equation 1), which is a polar ionic liquid. The process is reversed by simply purging with nitrogen, releasing C[O.sub.2] and regenerating the DBU/hexanol mixture. In order for the solvent switch to be effective, the choice of alcohol is critical. Smaller alcohols such as methanol lead to solids after treatment with C[O.sub.2], so more lipophilic alcohols like hexanol need to be employed for the reversible preparation of this interesting ionic liquid.

G-protein coupled receptors--stand up and be counted.

Despite the remarkable advances over the past decade in chemical biology, there are still large gaps in our knowledge of cell signalling. Part of the reason for this is the lack of available methods to image the cellular proteins and other constituents in real systems. For example, much of the information on cell signalling is extrapolated from artificially generated phospholipid membranes loaded with the proteins and chemical signals that are believed to comprise the signaling system.

A team of researchers led by John Pezacki, MCIC, and Linda Johnston, MCIC, at the Steacie Institute of Molecular Sciences (NRC) in Ottawa has recently shown that receptors and cellular proteins can actually be visualized in live cardiac cells called myocytes. Heart beats in all mammals are stimulated by the binding of catecholamine to beta adrenergic receptors in these cardiac cells. The NRC team, including Anatoli Ianoul, Donna Grant, Yanouchka Rouleau, and Mahmud Bani-Yaghoub, was able to actually visualize the location and clustering of these receptors using near field scanning optical microscopy (Figure 2). This technique allows researchers to "see" fluorescently labelled proteins on a length scale impossible with traditional optical microscopes. The size of the smallest feature that is observable is limited only by the size of the probe tip, which is on the order of 50 nm. In addition, by measuring the fluorescence intensity and comparing this to standards for single receptors, the NRC team is also able to quantify the number of receptors present in a single cluster. The other advantage of NSOM is that fluorescence at depths of less than 100 nm is undetected, so that only molecules in the membrane are observed.

[FIGURE 2 OMITTED]

In their paper (Nature Chemical Biology, 1 (2005) pp. 196-202), Pezacki and Johnston studied the association of the [[beta].sub.2] isoform of the [beta]-adrenergic receptors ([[beta].sub.2]AR) on clonal cardiac cells derived from embryonic rat hearts. [[beta].sub.2]AR receptors are part of the GPCR (G-protein coupled receptor) super family of proteins. These proteins are major targets for both drug and gene therapy, and thus have been well studied. However, the question of how a rapid, accurate signal results from a system in which signalling molecules and proteins have to diffuse through a sea of other proteins and ion channels that make up the cell membrane remains unanswered. One hypothesis is that signalling is aided by pre-organization. In their recent study, the NRC team has shown that the [[beta].sub.2]-adrenergic receptors do indeed preassociate in clusters supported by intercellular lipid rafts known as caveolae. These caveolae are rich in a protein known as caveolin-3. By fluorescently labelling both the [[beta].sub.2]AR and caveolin-3, Pezacki and Johnston were able to show that 15-20 percent of the [[beta].sub.2]AR was localized in caveolae. The [[beta].sub.2]AR that was not co-localized with caveolin-3 was clustered into domains on the order of ca. 150 nm. By quantifying the fluorescent signal observed, the number of receptors per cluster was determined to vary from between 12-72 for clusters in the range of 120-160 nm.

Interestingly, the NRC team showed that the preassembly of the [[beta].sub.2]AR into clusters occurred before the signalling molecule (in this case catecholamine) was introduced, implying that these receptors preorganize prior to stimulation so that they are in some way prepared for the hormone-induced signal cascade. In addition, the clusters did not change after exposure to the stimulant, so large-scale changes in the cluster are not required for the adrenergic response.

This study is the first to provide concrete evidence of the number of receptors pre-organizing in individual signalling clusters, known in the literature as signalosomes. This research adds weight to the argument that pre-organization of the key components of the signalling mechanism into individual clusters is responsible for the rapid response to chemical signals that is needed for efficient functioning of our cellular machinery.

Cathleen Crudden, MCIC, and Hans-Peter Loock, MCIC, are both associate professors of chemistry at Queen's University in Kingston, ON.
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Author:Crudden, Cathleen
Publication:Canadian Chemical News
Date:Nov 1, 2005
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