Sander J. Tans

Room-temperature transistor based on a single carbon nanotube

The use of individual molecules as functional electronic devices was first proposed in the 1970s (ref. 1). Since then, molecular electronics, has attracted much interest, particularly because it could lead to conceptually new miniaturization strategies in the electronics and computer industry. The realization of single-molecule devices has remained challenging, largely owing to difficulties in achieving electrical contact to individual molecules. Recent advances in nanotechnology, however, have resulted in electrical measurements on single molecules. Here we report the fabrication of a field-effect transistor—a three-terminal switching device—that consists of one semiconducting single-wall carbon nanotube, connected to two metal electrodes. By applying a voltage to a gate electrode, the nanotube can be switched from a conducting to an insulating state. We have previously reported similar behaviour for a metallic single-wall carbon nanotube operated at extremely low temperatures. The present device, in contrast, operates at room temperature, thereby meeting an important requirement for potential practical applications. Electrical measurements on the nanotube transistor indicate that its operation characteristics can be qualitatively described by the semiclassical band-bending models currently used for traditional semiconductor devices. The fabrication of the three-terminal switching device at the level of a single molecule represents an important step towards molecular electronics.

Empirical fitness landscapes reveal accessible evolutionary paths.

When attempting to understand evolution, we traditionally rely on analysing evolutionary outcomes, despite the fact that unseen intermediates determine its course. A handful of recent studies has begun to explore these intermediate evolutionary forms, which can be reconstructed in the laboratory. With this first view on empirical evolutionary landscapes, we can now finally start asking why particular evolutionary paths are taken.

Temperature-dependent resistivity of single-wall carbon nanotubes

Samples of single-wall carbon nanotubes containing tubes with an armchair wrapping have been produced and exhibit metallic behavior with an intrinsic resistivity which increases approximately linearly with temperature over a wide temperature range. Here we study the coupling of the conduction electrons to long-wavelength torsional shape fluctuations, or twistons. A one-dimensional theory of the scattering of electrons by twistons is presented which predicts an intrinsic resistivity proportional to the absolute temperature. Experimental measurements of the temperature dependence of the resistivity are reported and compared with the predictions of the twiston theory.

Electron–electron correlations in carbon nanotubes

Single-wall carbon nanotubes, are ideally suited for electron-transport experiments on single molecules because they have a very robust atomic and electronic structure and are sufficiently long to allow electrical connections to lithographically defined metallic electrodes. The electrical transport properties of single nanotubes and bundles of nanotubes have so far been interpreted by assuming that individual electrons within the nanotube do not interact, an approximation that is often well justified for artificial mesoscopic devices such as semiconductor quantum dots. Here we present transport spectroscopy data on an individual carbon nanotube that cannot be explained by using independent-particle models and simple shell-filling schemes. For example, electrons entering the nanotube in a low magnetic field are observed to all have the same spin direction, indicating spin polarization of the nanotube. Furthermore, even when the number of electrons on the nanotube is fixed, we find that variation of an applied gate voltage can significantly change the electronic spectrum of the nanotube and can induce spin flips. The experimental observations point to significant electron–electron correlations. We explain our results phenomenologically using a model that assumes that the capacitance of the nanotube depends on its many-body quantum state.

Stochasticity of metabolism and growth at the single-cell level

Elucidating the role of molecular stochasticity in cellular growth is central to understanding phenotypic heterogeneity and the stability of cellular proliferation. The inherent stochasticity of metabolic reaction events should have negligible effect, because of averaging over the many reaction events contributing to growth. Indeed, metabolism and growth are often considered to be constant for fixed conditions. Stochastic fluctuations in the expression level of metabolic enzymes could produce variations in the reactions they catalyse. However, whether such molecular fluctuations can affect growth is unclear, given the various stabilizing regulatory mechanisms, the slow adjustment of key cellular components such as ribosomes, and the secretion and buffering of excess metabolites. Here we use time-lapse microscopy to measure fluctuations in the instantaneous growth rate of single cells of Escherichia coli, and quantify time-resolved cross-correlations with the expression of lac genes and enzymes in central metabolism. We show that expression fluctuations of catabolically active enzymes can propagate and cause growth fluctuations, with transmission depending on the limitation of the enzyme to growth. Conversely, growth fluctuations propagate back to perturb expression. Accordingly, enzymes were found to transmit noise to other unrelated genes via growth. Homeostasis is promoted by a noise-cancelling mechanism that exploits fluctuations in the dilution of proteins by cell-volume expansion. The results indicate that molecular noise is propagated not only by regulatory proteins but also by metabolic reactions. They also suggest that cellular metabolism is inherently stochastic, and a generic source of phenotypic heterogeneity.

Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes

Having multiple peaks within fitness landscapes critically affects the course of evolution, but whether their presence imposes specific requirements at the level of genetic interactions remains unestablished. Here we show that to exhibit multiple fitness peaks, a biological system must contain reciprocal sign epistatic interactions, which are defined as genetic changes that are separately unfavorable but jointly advantageous. Using Morse theory, we argue that it is impossible to formulate a sufficient condition for multiple peaks in terms of local genetic interactions. These findings indicate that systems incapable of reciprocal sign epistasis will always possess a single fitness peak. However, reciprocal sign epistasis should be pervasive in nature as it is a logical consequence of specificity in molecular interactions. The results thus predict that specific molecular interactions may yield multiple fitness peaks, which can be tested experimentally.

Direct Observation of Chaperone-Induced Changes in a Protein Folding Pathway

How chaperone interactions affect protein folding pathways is a central problem in biology. With the use of optical tweezers and all-atom molecular dynamics simulations, we studied the effect of chaperone SecB on the folding and unfolding pathways of maltose binding protein (MBP) at the single-molecule level. In the absence of SecB, we find that the MBP polypeptide first collapses into a molten globulelike compacted state and then folds into a stable core structure onto which several α helices are finally wrapped. Interactions with SecB completely prevent stable tertiary contacts in the core structure but have no detectable effect on the folding of the external α helices. It appears that SecB only binds to the extended or molten globulelike structure and retains MBP in this latter state. Thus during MBP translocation, no energy is required to disrupt stable tertiary interactions.

Transcriptional Regulation by Competing Transcription Factor Modules

Gene regulatory networks lie at the heart of cellular computation. In these networks, intracellular and extracellular signals are integrated by transcription factors, which control the expression of transcription units by binding to cis-regulatory regions on the DNA. The designs of both eukaryotic and prokaryotic cis-regulatory regions are usually highly complex. They frequently consist of both repetitive and overlapping transcription factor binding sites. To unravel the design principles of these promoter architectures, we have designed in silico prokaryotic transcriptional logic gates with predefined input–output relations using an evolutionary algorithm. The resulting cis-regulatory designs are often composed of modules that consist of tandem arrays of binding sites to which the transcription factors bind cooperatively. Moreover, these modules often overlap with each other, leading to competition between them. Our analysis thus identifies a new signal integration motif that is based upon the interplay between intramodular cooperativity and intermodular competition. We show that this signal integration mechanism drastically enhances the capacity of cis-regulatory domains to integrate signals. Our results provide a possible explanation for the complexity of promoter architectures and could be used for the rational design of synthetic gene circuits.

Molecular transistors: Potential modulations along carbonnanotubes

True molecular-scale transistors have been realized using semiconducting carbon nanotubes, but no direct measurements of the underlying electronic structure of these have been made. Here we use a new scanning-probe technique to investigate the potential profile of these devices. Surprisingly, we find that the potential does not vary in a smooth, monotonic way, but instead shows marked modulations with a typical period of about 40 nm. Our results have direct relevance for modelling this promising class of molecular devices.

Calcium modulates force sensing by the von Willebrand factor A2 domain.

von Willebrand factor (VWF) multimers mediate primary adhesion and aggregation of platelets. VWF potency critically depends on multimer size, which is regulated by a feedback mechanism involving shear-induced unfolding of the VWF-A2 domain and cleavage by the metalloprotease ADAMTS-13. Here we report crystallographic and single-molecule optical tweezers data on VWF-A2 providing mechanistic insight into calcium-mediated stabilization of the native conformation that protects A2 from cleavage by ADAMTS-13. Unfolding of A2 requires higher forces when calcium is present and primarily proceeds through a mechanically stable intermediate with non-native calcium coordination. Calcium further accelerates refolding markedly, in particular, under applied load. We propose that calcium improves force sensing by allowing reversible force switching under physiologically relevant hydrodynamic conditions. Our data show for the first time the relevance of metal coordination for mechanical properties of a protein involved in mechanosensing.