Boosting research into new drugs: 'Smart materials' make proteins form crystals

Scientists have developed a new method to make proteins form crystals using 'smart materials' that remember the shape and characteristics of the molecule. The technique, reported today in Proceedings of the National Academy of Sciences, should assist research into new medicines by helping scientists work out the structure of drug targets.

The process of developing a new drug normally works by identifying a protein that is involved in the disease, then designing a molecule that will interact with the protein to stimulate or block its function. In order to do this, scientists need to know the structure of the protein that they are targeting.

A technique called X-ray crystallography can be used to analyse the arrangement of atoms within a crystal of protein, but getting a protein to come out of solution and form a crystal is a major obstacle. The number of proteins identified as potential drug targets is increasing exponentially as scientists make progress in the fields of genomics and proteomics, but with current methods, scientists have successfully obtained useful crystals for less than 20 per cent of proteins that have been tried.

Now researchers at Imperial College London and the University of Surrey have developed a more effective method for making proteins crystallise using materials called 'molecularly imprinted polymers' (MIPs). MIPs are compounds made up of small units that bind together around the outside of a molecule. When the molecule is extracted, it leaves a cavity that retains its shape and has a strong affinity for the target molecule.

This property makes MIPs ideal nucleants – substances that bind protein molecules and make it easier for them to come together to form crystals. Many substances have been used as nucleants before, but none are designed specifically to attract a particular protein.

"Proteins are very comfortable in solution," said Professor Naomi Chayen, from the Department of Surgery and Cancer at Imperial College London, who led the research. "They need some convincing to come out and form a crystal.

"MIPs help this process by using the protein as a template for forming its own crystal. Once the first molecule or group of molecules is held in place, other molecules can arrange themselves around it and start to build a crystal."

In the study, Professor Chayen and her colleagues found that six different MIPs induced crystallisation of nine proteins, yielding crystals in conditions that do not give crystals otherwise. They also tested whether MIPs would be effective at producing crystals from a series of preliminary trials for three target proteins for which scientists have not previously been able to obtain crystals of sufficient quality. The presence of MIPs gave rise to crystals in eight to 10 per cent of such trials, yielding valuable crystals that would have been missed using other known nucleants.

"Rational drug design depends on knowing the structure of the protein you're trying to target, and getting good crystals is essential for studying the structure," Professor Chayen said. "With MIPs we can get better crystals than we can with other methods, and also improve the probability of getting crystals from new proteins. This is a really significant innovation that could have a major impact on research leading to the development of new drugs."

More information: Saridakis et al. 'Protein crystallization facilitated by molecularly imprinted polymers' Proceedings of the National Academy of Sciences, published online 20 June 2011.

Provided by Imperial College London (news : web)

Metal particle generates new hope for hydrogen energy

Tiny metallic particles produced by University of Adelaide chemistry researchers are bringing new hope for the production of cheap, efficient and clean hydrogen energy.

Led by Associate Professor Greg Metha, Head of Chemistry, the researchers are exploring how the metal nanoparticles act as highly efficient catalysts in using solar radiation to split water into hydrogen and oxygen.

"Efficient and direct production of hydrogen from solar radiation provides a renewable energy source that is the pinnacle of clean energy," said Associate Professor Greg Metha. "We believe this work will contribute significantly to the global effort to convert solar energy into portable chemical energy."

The latest research is the outcome of 14 years of fundamental research by Associate Professor Metha's research group investigating the synthesis and properties of metal nanoparticles and how they work as catalysts at the molecular level.

The group works with metal "clusters" of about one-quarter of a nanometre in size -- less than 10 atoms. Associate Professor Metha said these tiny "magic clusters" act as super-efficient catalysts. Catalysts drive chemical reactions, reducing the amount of energy required.

"We've discovered ways of producing these tiny metallic clusters, we've explored their fundamental chemical activity, and now we are applying their catalytic properties to reactions which have great potential benefit for industrial use and the environment," said Associate Professor Metha.

PhD student Jason Alvino is exploring splitting water to make hydrogen (and oxygen) using solar energy -- a process that is not viable for industry development at the moment.

"We know this catalysis works very efficiently at the molecular level and now need to demonstrate it works on the macroscopic scale," said Associate Professor Metha.

"Splitting water to make hydrogen and oxygen requires a lot of energy and is an expensive process. We will be using solar radiation as the energy source, so there will be no carbon emissions and because the clusters work so efficiently as a catalyst, it will be a much better process.

"The ultimate aim is to produce hydrogen from water as a cheap portable energy source."

Associate Professor Metha said there were also other industrial chemical reactions that could be made feasible by these catalysts, using solar radiation as the energy source -- with potentially significant environmental benefits. One example was converting carbon dioxide into methane or methanol with water.

This project 'Solar Hydrogen: photocatalytic generation of hydrogen from water', has been funded under the three-year clean energy partnership between Adelaide Airport Ltd and the University's Centre for Energy Technology.

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The above story is reprinted (with editorial adaptations) from materials provided by University of Adelaide, via EurekAlert!, a service of AAAS.

High-energy density magnesium batteries for smart electrical grids

Magnesium-based batteries are, in theory, a very attractive alternative to other batteries.

Magnesium (Mg) is cheap, safe, lightweight, and its compounds are usually non-toxic. Mg is less expensive (metallic lithium [Li] costs about 24 times more than metallic Mg) because Mg is abundant in the Earth’s crust. Mg is safer because it is stable when exposed to the atmosphere. Mg provides a theoretical specific capacity of 2,205 ampere-hours/kilogram, making it an attractive high-energy density battery system.

Furthermore, it provides two electrons per atom and has electrochemical characteristics similar to Li (12 grams-per-Faraday [g/F], compared to 7 g/F for Li or 23 g/F for sodium).

Proper design and architecture should lead to Mg-based batteries with energy densities of 400-1,100 watt-hour per kilogram for an open circuit voltage in the range of 0.8 – 2.1 V, which would make it an attractive candidate for electrical grid energy storage and stationary back-up energy.

To make Mg-based batteries practical, researchers at DOE’s National Energy Technology Laboratory are developing novel alloys of Mg doped with different elements such as calcium, zinc, and yttrium. These alloys are being produced by melting and casting as well as powder metallurgy.

A new displacement reaction hypothesis, based on the reaction of nanostructured transition metal compounds with Mg, has resulted in a thermodynamically favorable reversible displacement reaction of transition metals and Mg-alloys.

Recent accomplishments include a new, intermetallic anode compound formulated by melting/casting and synthesis of a new MgMn1-xFexSiO4/C composite, and other transition metal oxide spinel cathode systems. Mg-based electrolytes and other ionic electrolytes have also been developed and are being tested.

Provided by National Energy Technology Laboratory

Compound may provide drug therapy approach for Huntington's disease

UT Southwestern Medical Center researchers have identified compounds that appear to inhibit a signaling pathway in Huntington's disease, a finding that may eventually lead to a potential drug therapy to help slow the progression of degenerative nerve disorders.

"Our studies have uncovered a new therapeutic target for Huntington's disease treatment and possibly for other neurodegenerative diseases," said Dr. Ilya Bezprozvanny, professor of physiology and senior author of the study, published in today's issue of Chemistry and Biology. "In addition, we now have this new series of compounds that gives us a tool to study the pathogenesis of Huntington's disease."

Huntington's disease is a fatal genetic disorder in which certain brain cells waste away. More than 250,000 people in the U.S. have the disorder or are at risk for it. The most common form is adult-onset, with symptoms usually developing in patients in their mid-30s and 40s.

The disease results in uncontrolled movements, psychiatric disturbance, gradual dementia and eventually death. There is no therapy available currently to slow the progression of the disease.

Scientists at UT Southwestern found that quinazoline-derived compounds effectively block what is known as the store-operated calcium entry signaling pathway, which was never before implicated in Huntington nerve cells but that might be a therapeutic target in the disease.

Dr. Bezprozvanny's laboratory research has contributed to growing scientific evidence that suggests abnormalities in neuronal calcium signaling play an important role in the development of Huntington's disease. UT Southwestern researchers demonstrated in the current study that the quinoline compounds – supplied by EnVivo – protected brain cells.

"If this holds, this compound can be considered to have potential therapeutic application for Huntington's," he said. "As we ultimately seek a cure, we are encouraged to have found something that may slow the progress or delay the onset of the disease."

Provided by UT Southwestern Medical Center (news : web)

Gold microflowers to enhance signals from molecules

Researchers have to place objects under study on suitable substrates to obtain a strong enhancement of electromagnetic radiation emitted by single molecules. A simple and cheap method to fabricate substrates for SERS spectroscopy has been discovered at the Institute of Physical Chemistry of the Polish Academy of Sciences. A key role in substrate fabrication play spherical gold aggregates -- flower-like micrometer-sized spheres.

Surface Enhanced Raman Spectroscopy (SERS) is a promising research tool that allows to enhance signals emitted by molecules by hundreds of thousands or even millions of times. „There is, however, no joy without annoy," says Dr Marcin Fiałkowski, associate professor at the Institute of Physical Chemistry of the Polish Academy of Sciences (IPC PAS). „To reach so high enhancement, the molecules must be placed on an appropriately shaped substrate. Under electron microscope, such substrates resemble peaked mountains, like Alps for example. The difference is that here the peak heights are measured in nanometres, and the mountains are covered not with snow but with a layer of gold."

At present no cheap, good and easy-to-use substrates for SERS analyses are available on the market and this is one of the factors inhibiting commercialization of the method. A promising solution to the problem seem to offer substrates developed recently at the Institute of Physical Chemistry of the PAS under the research project „Quantum nanostructures." The substrates are fabricated by depositing spherical, strongly ragged gold structures precipitating from solution, on a slide surface. When observed under electron microscope, these micrometer-sized spheres resemble flower buds composed of many gold petals.

The highest enhancement of a SERS signal is obtained when a molecule is placed in the meeting area of two "peaks" of the substrate. The effect can be hardly reached with existing mountain-like surfaces, as the peaks there are distinctly separated. The situation on the substrates made with gold flowers is different. „When ragged microflowers are deposited on the surface, they form thick, complex 3D structures with numerous meeting areas between the petals. That's why the signals emitted from our substrates are enhanced even by ten million times," stresses Katarzyna Winkler, a PhD student from the IPC PAS.

Equally crucial as the enhancement is the repeatability of signals obtained from a specific substrate. In that respect the layers of gold microflowers show excellent performance. The signals originating from molecules of the same type that are placed at different locations on the same substrate are very similar to each other, and this is not always the case for surfaces obtained with other methods. High signal repeatability has also been observed for substrates fabricated on various slides, using separately prepared solutions.

The fabrication of substrates using gold flowers is fast, simple and cheap, does not require to use neither robots nor clean rooms. "The reaction mixture contains only a gold salt and a reducing agent, mixed in an appropriate mixing ratio. The role of the reducing agent is to reduce gold cations to metallic gold," says Winkler. What remains is to immerse a roughened slide in so prepared solution. The deposition of gold flowers is usually completed within one hour, and the substrate is ready for use on the next day.

The method of covering surfaces with gold microflowers designed for SERS applications has been filed for patenting. The present goal of the researchers from the Institute of Physical Chemistry of the PAS is to develop substrates that can be used repeatedly in measurements involving various analytes. For that purpose, methods to wash out analytes while leaving the substrate structure intact are being developed.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Institute of Physical Chemistry of the Polish Academy of Sciences, via AlphaGalileo.