Molecular model of the neural dopamine transporter

The dopamine transporter (DAT) regulates the action of dopamine by reuptake of the neurotransmitter into presynaptic neurons, and is the main molecular target of amphetamines and cocaine. DAT and the Na⁺/H⁺ antiporter (NhaA) are secondary transporter proteins that carry small molecules across a cell membrane against a concentration gradient, using ion gradients as energy source. A 3-dimensional projection map of the E. coli NhaA has confirmed a topology of 12 membrane spanning domains, and was previously used to construct a 3-dimensional NhaA model with 12 trans-membrane -helices (TMHs). The NhaA model, and site directed mutagenesis data on DAT, were used to construct a detailed 3-dimensional DAT model using interactive molecular graphics and empiric force field calculations. The model proposes a dopamine transport mechanism involving TMHs 1, 3, 4, 5, 7 and 11. Asp79, Tyr252 and Tyr274 were the primary cocaine binding residues. Binding of cocaine or its analogue, (–)-2-carbomethoxy-3-(4-fluorophenyl)tropane (CFT), seemed to lock the transporter in an inactive state, and thus inhibit dopamine transport. The present model may be used to design further experimental studies of the molecular structure and mechanisms of DAT and other secondary transporter proteins.     

The role of the active site tyrosine in the mechanism of lytic polysaccharide monooxygenase

Catalytic breakdown of polysaccharides can be achieved more efficiently by means of the enzymes lytic polysaccharide monooxygenases (LPMOs). However, the LPMO mechanism has remained controversial, preventing full exploitation of their potential. One of the controversies has centered around an active site tyrosine, present in most LPMO classes. Recent investigations have for the first time obtained direct (spectroscopic) evidence for the possibility of chemical modification of this tyrosine. However, the spectroscopic features obtained in the different investigations are remarkably different, with absorption maximum at 420 and 490 nm, respectively. In this paper we use density functional theory (DFT) in a QM/MM formulation to reconcile these (apparently) conflicting results. By modeling the spectroscopy as well as the underlying reaction mechanism we can show how formation of two isomers (both involving deprotonation of tyrosine) explains the difference in the observed spectroscopic features. Both isomers have a [TyrO–Cu–OH]⁺ moiety with the OH in either the cis- or trans-position to a deprotonated tyrosine. Although the cis-[TyrO–Cu–OH]⁺ moiety is well positioned for oxidation of the substrate, preliminary calculations with the substrate reveal that the reactivity is at best moderate, making a protective role of tyrosine more likely.

With QM/MM, we investigate the mechanism of tyrosine deprotonation in lytic polysaccharide monooxygenases. Our results support deprotonation and our calculated UV-vis spectra show that two isomers must be formed to match recent experiments.     

The New Macromolecular Femtosecond Crystallography (MFX) Instrument at LCLS

Macromolecular X-ray crystallography has developed, since its first use over 50 years ago to solve the structure of myoglobin, into a widely used method with broad impact in biological sciences and in society. It is today the primary technique used to obtain structural information on biomolecules that can shed light on their function and this information is often used in biomedical applications such as drug design. As this article is written, the Protein Data Bank [1 F.C. Bernstein, Journal of Molecular Biology 112(3), 535–542 (1977).[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]] has just reached the milestone of 100,000 deposited X-ray structures, with a continuing trend for an ever-increasing number of structures every year. The primary contribution to this success and the increasing number of X-ray structures is the broad availability of synchrotron radiation sources with many dedicated beamlines around the world providing rapid and efficient data collection along with standard data analysis tools capable of fast data interpretation.     

Protocell Communication through the Eyes of Synthetic Organic Chemists

The bottom-up fabrication of synthetic cells (protocells) from molecules and materials, is a major challenge of modern chemistry. A significant breakthrough has been the engineering of protocells capable of chemical communication using bio-derived molecules and ex situ stabilised cell machineries. These, however, suffer from short shelf-lives, high costs, and require mild aqueous conditions. In this Concept Article we analyse the chemistry at the heart of protocell communication to highlight new opportunities for synthetic chemists in protocell engineering. Specifically, we (i) categorise the main bio-derived chemical communication machineries in enzyme cascades, DNA strand displacement, and gene-mediated communication; (ii) review the chemistries of these signal transduction machineries; and (iii) introduce new types of bio-inspired, fully synthetic artificial enzymes to replace their natural counterparts. Developing protocells that incorporate synthetic analogues of bio-derived signal transduction machineries will improve the robustness, stability, and versatility of protocells, and broaden their applications to highly strategic fields such as photocatalysis and fine chemicals production.     

High detectivity dilute nitride strained layer superlattice detectors for LWIR and VLWIR applications

This paper will describe the first-of-a-kind development and demonstration of dilute nitride strained layer superlattice detectors with detectivity as high as 4 × 10¹⁰ cm Hz^1/2/W and cut-off wavelength of 11-μm for an LWIR design and a cut-off wavelength of 22-μm for a VLWIR design. The developed dilute nitride SLS detectors are based on ultra-low leakage dilute nitride epitaxial layers and/or strained layer superlattices (SLS) of InAs/InAsSbN and InAs/GaInSbN that could enable high VLWIR detectivities at elevated temperatures and at low cost.     

Large scale manufacturing of compound semiconductors by MOVPE

As more compound semiconductor devices reach large volume manufacturing levels, a trend toward the use of the MOVPE technique is clear. In this paper we examine the criteria needed for MOVPE equipment suitable for large scale manufacturing. We find that although uniformity and device performance are necessary, reproducibility is also critical, along with high throughput and low operating costs. These points are illustrated by actual examples including MMIC power amplifiers, HB-LEDs, and solar cells. A realistic COO model provides a tool for evaluating MOVPE systems of different capacities. In situ control of key parameters during growth is now feasible, and will become an important method for increasing reproducibility and throughput. Lastly we look at the prospects for automation, for decreasing labor costs as well as wafer handling. This is likely to first have an impact on systems for the growth of electronic device structures on large (100 and 150 mm) wafers.     

30th annual SSRL users’ meeting and workshops

Over the last 15 years, many 3^rd generation SR sources have been built throughout the world, either at energies of 1/2.5 or at 6 (ESRF, European Synchrotron Radiation Facility), 7 (APS, Advanced Photon Source), or 8 (SPring-8) GeV. These sources are characterized by a horizontal emittance in the range of 3–7 nm.rad with less than 1% coupling. With in-vacuum undulators, this kind of emittance enables the obtainment of brilliances between 10¹⁹–10²¹ph/s/mm²/mrad²/0.1% bw.     

New products

Arosy future was forecast for Brookhaven National Laboratory's (BNL) user facilities at the first-ever joint meeting of the user communities for the National Synchrotron Light Source (NSLS) and the Center for Functional Nanomaterials (CFN), held May 15–17, 2006.     

A nonacid degradable linker for solid-phase synthesis

Synthesis and applications of two new nonacid degradable linkers as an alternative to the Wang linker for solid-phase synthesis are described. Resin from linker 2 looks superior to linker 1 in terms of yields for both anchoring of the first building block and cleavage and in terms of higher purity of the final product. Use of linker 2 avoids side reactions associated with the use of Wang resin due to an undesired cleavage during final acid treatment.