Metadynamics technique offers insight into mineral growth and dissolution

By using a novel technique to better understand mineral growth and dissolution, researchers at the Department of Energy's Oak Ridge National Laboratory are improving predictions of mineral reactions and laying the groundwork for applications ranging from keeping oil pipes clear to sequestering radium.

The mineral barite was examined to understand mineral growth and dissolution generally, but also because it is the dominant scale-forming mineral that precipitates in oil pipelines and reservoirs in the North Sea. Oil companies use a variety of compounds to inhibit scale formation, but a better understanding of how barite grows could enable them to be designed more efficiently.

Additionally, barium can trap radium in its crystal structure, so it has the potential to contain the radioactive material.

In a paper featured on this month's cover of the Journal of the American Chemical Society, the ORNL-led team studied barite growth and dissolution using metadynamics, a critical technique that allows researchers to study much slower reactions than what is normally possible.

"When a mineral is growing or dissolving, you have a hard time sorting out which are the important reactions and how they occur because there are many things that could be happening on the surface," said Andrew Stack, ORNL geochemist and lead author on the paper. "We can't determine which of many possible reactions are controlling the rate of growth."

To overcome this hurdle, ORNL Chemical Sciences Division's Stack started with molecular dynamics, which can simulate energies and structures at the atomic level. To model a mineral surface accurately, the researchers need to simulate thousands of atoms. To directly measure a slow reaction with this many atoms during mineral growth or dissolution might take years of supercomputer time. Metadynamics, which builds on molecular dynamics, is a technique to "push" reactions forward so researchers can observe them and measure how fast they are proceeding in a relatively short amount of computer time.

With the help of metadynamics, the team determined that there are multiple intermediate reactions that take place when a barium ion attaches or detaches at the mineral surface, which contradicts the previous assumption that attachment and detachment occurred all in a single reaction.

"Without metadynamics, we would never have been able to see these intermediates nor determine which ones are limiting the overall reaction rate," Stack said.

To run computer simulations of mineral growth, researchers used the Large-scale Atomic/Molecular Massively Parallel Simulator, a molecular dynamics code developed by Sandia National Laboratories. Co-authors on the paper are the Curtin University (Australia) Nanochemistry Research Institute's Paolo Raiteri and Julian Gale.

In a podcast (http://pubs.acs.org/JACSbeta/coverartpodcasts) from the American Chemical Society, Andrew Stack talks about his metadynamics research.

The research was sponsored by the DOE Office of Science. ORNL is managed by UT-Battelle for the Department of Energy's Office of Science.

Story Source:

The above story is reprinted from materials provided by DOE/Oak Ridge National Laboratory.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Andrew G. Stack, Paolo Raiteri, Julian D. Gale. Accurate Rates of the Complex Mechanisms for Growth and Dissolution of Minerals Using a Combination of Rare-Event Theories. Journal of the American Chemical Society, 2012; 134 (1): 11 DOI: 10.1021/ja204714k

E. coli packs a punch - an intestinal insight from ISIS

Commonly found in the intestines of humans and animals, E. coli is normally considered to be a ‘helpful’ bacterium that aids digestion.  However, it can also cause vomiting and diarrhoea, and can be a serious illness for young children, the elderly and those with vulnerable immune systems.  In 2010, 793 incidents of the O157 strain of E. coli were recorded by the Health Protection Agency, but this is thought to only represent a fraction of actual cases because most go unreported.

Discovering how antibacterial proteins attack harmful bacteria is important for establishing new methods of drug delivery. Antibacterial proteins often have to travel across a waterproof cell membrane to reach their target. E. coli bacteria use a similar mechanism when attacking each other so it makes a good comparable study for observing this behaviour.

A bacterial cell is surrounded by a cell membrane that acts as a barrier to hold nutrients and cell components inside, and protect the cell from attack.  The E. coli membrane is particularly difficult to pass through as it is a hydrophobic double layer making it twice as hard for the intruders to penetrate. To penetrate these barriers, E. coli bacteria secrete toxic proteins called Colicins. Just one Colicin can be enough to kill an E. coli bacterium – this is no mean feat as the E. coli bacterium is 400,000 times heavier than the Colicin protein.

For the first time, experiments carried out at ISIS by a team from Newcastle University and funded by the Wellcome Trust have revealed a ‘side view’ of the process that one type of Colicin (Colicin N) uses to kill E. coli bacteria.  The experiments allowed the progress of the Colicin N to be followed as it travelled through the membrane.  More conventional study methods only allow a surface-view of the membrane.  Colicin N specialises in punching a hole through the inner membrane of its target E. coli bacterium. Normally Colicin N would not be able to do this because it is too big to fit through the narrow food-entry pores in the outer membrane of the E. coli.  Results from these experiments have discovered that Colicin hijacks the pore-forming protein Ompf in the outer membrane of the bacteria and then squeezes down the side to reach the inner membrane which it then attacks.

“Neutron scattering techniques were able to show us the insertion of Colicin N into the hydrophobic membrane. Using neutrons allowed us to get a side view of the process, which is important when following proteins across a barrier” said Jeremy Lakey, Professor of Structural Biochemistry at Newcastle University.

Professor Lakey and his team plan to conduct further studies at ISIS to observe later stages of the process.  The results of this research (published in the Journal of Biological Chemistry) will be used to develop new, more effective ways to treat life-threatening illnesses and ultimately help save lives.

Provided by Science and Technology Facilities Council (news : web)

TACC supercomputers help researchers find deeper insight into structure and behavior of protein, DNA and RNA

Analytical ultracentrifugation (AUC) experiments spin samples at very high speeds to study how large molecules such as proteins, DNA and RNA, act in solution. Under the influence of centrifugal forces up to 250,000 times as strong as Earth's gravity, materials undergo sedimentation and diffusion processes over time, revealing aspects of the individual molecules' natures.

These processes are essential measurements for biochemists: a way to understand how molecules behave under physiological solution conditions. And 85 years later, scientists are still finding ways to make the analytic ultracentrifuge more useful.

Unlike traditional microscopy where samples are bound to a microscope grid, or x-ray crystallography where they are locked into a crystal with packing forces that may distort the molecule, AUC experiments preserve the native structures and configurations of molecules. They do this by analyzing molecules in solution, where they can dynamically interact and bind to other molecules, or react to environmental changes such as temperature, ionic strength or pH.

Enlarge

A van Holde - Weischet analysis providing a differential (green) and integral (red) sedimentation profile for a sedimentation velocity experiment performed on a restriction digest of a DNA fragment. In the integral distribution, the vertical axis indicates the relative concentration of each species, while the horizontal axes indicates the sedimentation coefficient.

"If you don't have a way to measure your molecule in solution, then a lot of this will escape you," said Borries Demeler, associate professor of biochemistry at The University of Texas Health Sciences Center and director of the Center for Analytical Ultracentrifugation of Macromolecular Assemblies (CAUMA). "By studying biological macromolecules in a solution, it is possible to observe reactions, and follow conformational changes."

AUC is also a very versatile tool to study composition. Even trace amounts of impurities can be resolved by AUC, and mixtures can be analyzed to identify molecular weight and shape distributions.

Initially, the analysis of centrifugal experiments was done manually, but with the emergence of computers and sensors in the 1960s, more precise ways of assessing experimental results were developed. Today's optical systems can follow sedimenting and diffusing molecules by detecting ultraviolet and visible absorption, the refractive index, and fluorescence emission. The signals are captured digitally to allow them to be analyzed by computer.

For more than two decades, Demeler has worked at the intersection of the physical (spinning samples) and the virtual (supercomputer simulations), investigating new methods and developing software to help researchers make the most of their AUC experiments.

As the director of CAUMA, Demeler works with hundreds of investigators around the world, including biophysicists studying the structure and function of biological macromolecules and assemblies, material scientists trying to make more efficient solar cells, and the pharmaceutical industry evaluating the stability of their formulations. As a collaborator in many research projects, he is continually challenged by new research questions and enjoys the interactions with many fascinating scientists.

His largest impact, however, is felt through the creation of the UltraScan software package, and the development of the UltraScan LIMS portal through which researchers analyze their experimental data over the web using advanced computing methods and systems.

"I started writing the very first version of UltraScan using BASIC on a 286 PC back in 1988," Demeler recalled, "and it's gone through many iterations. "

In 2004, Demeler and his colleague, Emre Brookes, began parallelizing the code so it could run on large-scale computer clusters. This dramatically sped up the rate at which samples could be analyzed. It also enabled the researchers to develop high-resolution analysis methods and address an entirely new class of research questions that widened the application of the AUC method.

Enlarge

A single scan of a sedimentation velocity experiment with semiconducting nanoparticles collected with a novel multiwavelength detector. This novel detector can resolve not only composition by hydrodynamic separation, but also by spectral decomposition, and is developed in Dr. Helmut C?lfen's laboratory at the University of Konstanz in Germany.

UltraScan doesn't just allow researchers to measure the diffusion and sedimentation processes; it decodes the meaning of these processes and uncovers hidden characteristics of the sample.

"We often don't know what really is in a solution provided by a collaborator, and we need to get the most out of our analysis," Demeler explained. "To fit the data, we simulate many different components that may be in the solution, and ask the question, ‘How much of each component is present in the actual experiment?'"

This process can be done on a regular computer, but the answers that such a process generates lack the resolution required for clinical or industrial investigations, or simply take too long to complete.

"To squeeze out the last drop of information, you need to go through quite a bit more computational expense," Demeler said. "This is where we kick in with our methods."

UltraScan's numerical methods extract noise, narrow the parameter space, compare multiple experiments, and determine the uncertainty of the result.

While some analyses are performed on a small development cluster in Demeler's lab, the capacity is insufficient to address the most challenging problems, and to satisfy all of the demand for analysis among a growing international group of AUC users. Instead, Demeler relies on the computing systems of the National Science Foundation funded Extreme Science and Engineering Discovery Environment (XSEDE), the most powerful, and robust collection of integrated advanced digital resources and services in the world.

Demeler's simulations use anywhere between 40 and 14,000 processors simultaneously, speeding up the analytic processing by as much as 10,000 times. In 2010-2011, Demeler used 3.5 million computing hours on the Ranger and Lonestar supercomputers at the Texas Advanced Computing Center (TACC) to perform simulations for the open science community.

"It's not just reserved for biochemists and biophysicists," Demeler said. "We might work with a clinician, perform measurements for materials science, or measure the binding strength of a new drug to its target."

Demeler pointed to a recent example of work he is doing with researchers in Germany characterizing fluorescent nanoparticles made out of cadmium telluride crystals for use in solar panels. Using a new detector developed by a collaborator at the Max Planck Institute, he was able to not only measure the hydrodynamic properties, but also observe their individual absorption spectra, and correlate absorbance properties with particle size.

Enlarge

2-dimensional spectrum - Monte Carlo analysis of a sedimentation velocity experiment. In this experiment two interacting proteins (A and B) were titrated against each other, resulting in a non-globular complex. In the upper left, protein A is shown to generate several globular oligomers. Addition of protein B results in the appearance of a non-globular peak (upper right). An increasing amount of protein B causes an increase of the AB complex (lower left). At the highest concentration of protein B, the lowest molecular weight form of the globular species has completely disappeared, and been converted into the non-globular species. This work was performed in collaboration with Bettie Sue Master's laboratory at UTHSCSA.

Whether the application is nanoparticles for industry or biomarkers in blood, AUC together with UltraScan is an incredibly useful tool. But creating the software and algorithms wasn't the final step. Many potential users of AUC and UltraScan are not computer scientists, and Demeler believed a fear of the supercomputer command line interface would prevent them from using the software.

"To get people to adopt this technology, you have to make it easy for them," he said. "It needs to be extremely robust, user-friendly and intuitive."

Through an Advanced Support for TeraGrid Applications (ASTA) grant from the NSF, staff at Indiana University helped Demeler develop a web-based gateway where researchers log in, access their data, and submit jobs as if they were running a very simple web application.

"The user only has to be familiar with the basic analysis procedure and a web browser; familiarity with Unix supercomputing is not required," Demeler said. "Our users really like this approach."

Eighty-five years after its inception, the evolution of the analytic ultracentrifuge continues. The latest challenge involves finding ways to integrate AUC results with results from other solution methods.

Demeler and Brookes are developing an integrated system combining molecular dynamics with hydrodynamic and small angle scattering simulations to screen a large variety of structural conformations against experimental data. This will give a large pool of researchers new insight into the structure and function of molecules under study.

"The knowledge obtained should enhance our understanding of biomolecular processes, including disease processes, which can lead to improved prevention and treatment," said Emre Brookes. "None of this would be feasible without the vast computational resources available through XSEDE."

Demeler and Brookes' long-term dream is to create a way to integrate all known observational methods — including x-ray crystallography, nuclear magnetic resonance imaging, and calorimetry — to see more deeply than we currently do, without losing sight of the natural conditions under which molecules exist.

"It's like taking a picture of an object from many different angles, and every time you take a picture you see something else that adds to the whole," Demeler said. "By combining them all, the new picture will tell you something you didn't know before."

More information: To read more about the challenges of biochemistry and the role of AUC in protein study, see Demeler's recent commentary in the June 2011 edition of Nature Chemical Biology.

The story is courtesy of Faith Singer-Villalobos @ Texas Advanced Computing Center (TACC).

Provided by University of Texas at Austin (news : web)

Chemistry: New insight into 100-year-old Haber-Bbosch process of converting nitrogen to ammonia

For the past 100 years, the Haber-Bosch process has been used to convert atmospheric nitrogen into ammonia, which is essential in the manufacture of fertilizer. Despite the longstanding reliability of the process, scientists have had little understanding of how it actually works. But now a team of chemists, led by Patrick Holland of the University of Rochester, has new insight into how the ammonia is formed. Their findings are published in the latest issue of Science.

Holland calls nitrogen molecules "challenging." While they're abundant in the air around us, which makes them desirable for research and manufacturing, their strong triple bonds are difficult to break, making them highly unreactive. For the last century, the Haber-Bosch process has made use of an iron catalyst at extremely high pressures and high temperatures to break those bonds and produce ammonia, one drop at a time. The question of how this works, though, has not been answered to this day.

"The Haber-Bosch process is efficient, but it is hard to understand because the reaction occurs only on a solid catalyst, which is difficult to study directly," said Holland. "That's why we attempted to break the nitrogen using soluble forms of iron."

Holland and his team, which included Meghan Rodriguez and William Brennessel at the University of Rochester and Eckhard Bill of the Max Planck Institute for Bioinorganic Chemistry in Germany, succeeded in mimicking the process in solution. They discovered that an iron complex combined with potassium was capable of breaking the strong bonds between the nitrogen (N) atoms and forming a complex with an Fe3N2 core, which indicates that three iron (Fe) atoms work together in order to break the N-N bonds. The new complex then reacts with hydrogen (H2) and acid to form ammonia (NH3) -- something that had never been done by iron in solution before.

Despite the breakthrough, the Haber-Bosch process is not likely to be replaced anytime soon. While there are risks in producing ammonia at extremely high temperatures and pressures, Holland points out that the catalyst used in Haber-Bosch is considerably less expensive than what was used by his team. But Holland says it is possible that his team's research could eventually help in coming up with a better catalyst for the Haber-Bosch process -- one that would allow ammonia to be produced at lower temperatures and pressures.

At the same time, the findings could have a benefit far removed from the world of ammonia and fertilizer. When the iron-potassium complex breaks apart the nitrogen molecules, negatively charged nitrogen ions -- called nitrides -- are formed. Holland says the nitrides formed in solution could be useful in making pharmaceuticals and other products.

Story Source:

The above story is reprinted from materials provided by University of Rochester.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

M. M. Rodriguez, E. Bill, W. W. Brennessel, P. L. Holland. N2 Reduction and Hydrogenation to Ammonia by a Molecular Iron-Potassium Complex. Science, 2011; 334 (6057): 780 DOI: 10.1126/science.1211906

Note: If no author is given, the source is cited instead.

New technology enables molecular-level insight into carbon sequestration

 

Flaviu Turcu co-invented a novel NMR system for carbon sequestration research applications with EMSL staff, David Hoyt (Principal Investigator) and Jesse Sears, and PNNL colleagues, Jian Zhi Hu and Kevin Rosso. Turcu, pictured above, holds the high-pressure MAS rotor and stands behind the high-pressure rotor loading reaction chamber pieces of the system.

Carbon sequestration is a potential solution for reducing greenhouse gases that contribute to climate change, but its scientific challenges are complex. Analytical tools are needed that provide information about the mineral-fluid interactions of carbon dioxide (CO2) at the molecular level.

As part of Pacific Northwest National Laboratory (PNNL)'s Carbon Sequestration Initiative, a team of EMSL and PNNL researchers developed and patented such a tool—a unique high-pressure magic angle spinning (MAS) nuclear magnetic resonance (NMR) capability that operates in conditions characteristic of geologic carbon sequestration.

Described in the September 2011 issue of the Journal of Magnetic Resonance, this new technology consists of a reusable high-pressure MAS rotor, a high-pressure rotor loading/reaction chamber for in situ sealing and reopening of the high-pressure MAS rotor, and a MAS probe with a localized radiofrequency coil for background signal suppression.

This new capability can help determine reaction intermediates and final products that occur during mineral dissolution reactions relevant to the geologic disposal of CO2, as these researchers reported in the July 2011 issue of the International Journal of Greenhouse Gas Control.

Identifying reaction intermediates is not possible using only ex situ measurements and is critical to determining the mechanisms of mineral dissolution at high pressures. This new capability has the potential to further the exploration of solid-state chemistry at new levels of high pressure and temperature in many science areas.

More information: References: Hoyt DW, RVF Turcu, JA Sears, KM Rosso, SD Burton, AR Felmy, and JZ Hu. 2011. “High-pressure Magic Angle Spinning Nuclear Magnetic Resonance,” Journal of Magnetic Resonance, DOI:10.1016/j.jmr.2011.07.019

Hoyt DW, JA Sears, RVF Turcu, KM Rosso, and JZ Hu. 2011. U.S. Patent submission E-16894, “Devices and Process for High-Pressure Magic Angle Spinning Nuclear Magnetic Resonance,” filed July 28, 2011 (provisional patent submitted December 13, 2010).

Kwak JH, JZ Hu, RVF Turcu, KM Rosso, ES Ilton, C Wang, JA Sears, MH Engelhard, AR Felmy, and DW Hoyt. 2011. "The Role of H2O in the Carbonation of Forsterite in Supercritical CO2." International Journal of Greenhouse Gas Control 5:1081-1092.

Provided by Environmental Molecular Sciences Laboratory (news : web)

New insight into how disordered solids deform

 In solid materials with regular atomic structures, figuring out weak points where the material will break under stress is relatively easy. But for disordered solids, like glass or sand, their disordered nature makes such predictions much more daunting tasks.

Now, a collaboration combining a theoretical model with a first-of-its kind experiment has demonstrated a novel method for identifying "soft spots" in such materials. The findings from University of Pennsylvania and Syracuse University physicists may lead to better understanding of the principles that govern materials responses ranging from failure of glasses to earthquakes and avalanches.

The experimental research was conducted by professors Arjun G. Yodh and Andrea J. Liu, along with post-doctoral associates Ke Chen, Wouter G. Ellenbroek and Zexin Zhang and graduate student Peter J. Yunker, all of the Department of Physics and Astronomy in Penn's School of Arts and Sciences. They collaborated with Lisa Manning of the Department of Physics at Syracuse. Liu and Manning described the theoretical model in a separate study.

Both studies appear in the journal Physical Review Letters.

For materials with well ordered, crystalline internal structures, such as diamonds or most metals, identifying soft spots is easy; weak, disordered sections stick out like a sore thumb.

"In perfect crystalline materials, atoms are in well-defined positions. If you give me the position of one atom, I can tell you the position of another with precision," Yodh said. "There's also a well defined theory about what's happening with defects in crystals when stresses are applied to them."

"There's no periodicity in glass, however," Chen said. "You can't look at it and say, 'This part looks different than the rest,' because there is no background pattern to compare it with."

With physical structure a dead end for identifying soft spots, the physicists turned to another property: vibrations. Though the word "solid" is synonymous with "unmoving," the particles that make up solid matter are constantly vibrating. And like the different tones of guitar strings, there are many different ways particles in a solid can vibrate. These are known as "vibration modes."

For crystalline materials, the regular patterns of atoms lead to uniform patterns of vibrations within the material; nearly all particles are involved in a typical vibration. In disordered materials, with their unevenly spaced particles, particles in different regions vibrate differently, producing some new and different vibration modes, particularly at low frequencies.

"We can determine the spatial patterns of the different vibrations in our experiment, and then we can find out whether some of them, particularly low frequency vibrations, are connected with rearrangements or failure of the material when it is stressed," Chen said.

Manning and Liu developed a simulation to test this kind of correlation under idealized conditions. They were able to show that certain regions highlighted by low frequency vibration modes acted like defects in disorganized materials and that these defects were good candidates for where the material would fail when stressed.

"We showed, for the first time, a correlation between the soft spot population and rearrangements under stress," Manning said. "This is something people have been looking for over the past 30 or 40 years."

Though the success of the simulation was an exciting result by itself, it was only a first step. Real-world systems have additional layers of complexity, notably temperature and related thermal fluctuations that can rapidly change the interactions between neighboring particles and thus the system's vibrational patterns.

"It was not at all obvious that the soft spots we found in the simulation would still exist in the presence of thermal fluctuations, which are unavoidable in the real world," Liu said. "Thermal fluctuations, for example, might have caused the soft spots to be wiped out too rapidly to be used for analysis."

To see if this was the case, Chen developed an experimental system with many features similar to the one in the simulation. At its core was a colloidal glass, an effectively two-dimensional material consisting of a single disordered layer of soft plastic particles tightly packed together.

By analyzing video of the particles' motion in the colloidal glass as observed under a microscope, Chen was able to calculate the vibration patterns and then use Manning and Liu's model to locate regions vulnerable to rearrangement once the glass was put under stress. He then compared these regions to the rearrangements that actually happened.

Just as in the simulation, the soft spots predicted candidates for rearrangement, as some of the identified soft spots remained intact while others deformed. The experiment thus provides a new basis -- low frequency vibration modes -- for analyzing real-world disordered solids.

"Low frequency vibrations correspond to areas with weak interaction between particles, and because of these weak interactions their structure is less stable. When they're perturbed there is less resistance from their neighbors." Chen said.

Disordered solids are much more common than ordered ones, so having a working theory of how, why and where they break has many potential applications.

"You can bend a metal spoon, but you can't bend one made out of glass without breaking it. If you can understand how disordered solids fail, you might be able to make them tougher," Yodh said.

The research was funded by the National Science Foundation, including the Penn Materials Research Science and Engineering Center, the Princeton Center for Theoretical Science at Princeton University, NASA and the U.S. Department of Energy.

Zexin Zhang has appointments with the CNRS-Rhodia-UPenn Complex Assemblies of Soft Matter collaboration and the Center for Soft Condensed Matter Physics and Interdisciplinary Research, Soochow University, China.

Story Source:

The above story is reprinted (with editorial adaptations ) from materials provided by University of Pennsylvania.

Journal References:

Ke Chen, M. Manning, Peter Yunker, Wouter Ellenbroek, Zexin Zhang, Andrea Liu, A. Yodh. Measurement of Correlations between Low-Frequency Vibrational Modes and Particle Rearrangements in Quasi-Two-Dimensional Colloidal Glasses. Physical Review Letters, 2011; 107 (10) DOI: 10.1103/PhysRevLett.107.108301M. Manning, A. Liu. Vibrational Modes Identify Soft Spots in a Sheared Disordered Packing. Physical Review Letters, 2011; 107 (10) DOI: 10.1103/PhysRevLett.107.108302

 

Sweet insight: New discovery could speed drug development

The surface of cells and many biologically active molecules are studded with sugar structures that are not used to store energy, but rather are involved in communication, immunity and inflammation. In a similar manner, sugars attached to drugs can enhance, change or neutralize their effects, says Jon Thorson, a professor of pharmaceutical sciences at the University of Wisconsin-Madison School of Pharmacy.

Thorson, an expert in the attachment and function of these sugars, says that understanding and controlling them has major potential for improving drugs, but that researchers have been stymied because many novel sugars are difficult to create and manipulate. "The chemistry of these sugars is difficult, so we have been working on methods to make it more user friendly," he says.

Now, in a study published online in Nature Chemical Biology on Aug. 21, Thorson, graduate student Richard Gantt and postdoctoral fellow Pauline Peltier-Pain have described a simple process to separate the sugars from a carrier molecule, then attach them to a drug or other chemical. The process also causes a color change only among those molecules that have accepted the sugar. The change in color should support a screening system that would easily select out transformed molecules for further testing. "One can put 1,000 drug varieties on a plate and tell by color how many of them have received the added sugar," Thorson says.

Attached sugars play a key role in pharmacy, says Thorson. Not only can they change the solubility of a compound, but "there are transporters in the body that specifically recognize certain sugars, and pharmaceutical companies have taken advantage of this to direct molecules toward specific tissue or cell types. If we can build a toolbox that allows us to make these molecules on demand, we can ask, 'What will sugar A do when it's attached to drug B?'"

And although the new study was focused more on an improved technique rather than the alteration of drugs, Thorson adds that it does describe the production of some "really interesting sugar-appended drugs: anti-virals, antibiotics, anti-cancer and anti-inflammatory drugs. Follow-up studies are currently under way to explore the potential of these analogs."

The new molecules included 11 variants of vancomycin, a powerful antibiotic, each distinguished by the nature and number of attached sugars.

The essence of the new process is its starting point: a molecule that changes the energy dynamics of the sugar-attachment reaction, Thorson says. "This is one of the first systematic studies of the equilibrium of the reaction, and it shows we can drive it forward or in reverse, depending on the molecule that we start with."

In a single test tube, the new technique is able to detach the sugar from its carrier and reattach it to the biological target molecule, Thorson says. "Sugars are involved a vast range of biology, but there are still many aspects that are not well understood about the impact of attaching and removing sugars, partly because of the difficulty of analyzing and accessing these species."

Making variants of potential and existing drugs is a standard practice for drug-makers, and a recently published study by Peltier-Pain and Thorson revealed that attaching a certain sugar to the anti-coagulant Warfarin destroys its anti-clotting ability. The transformed molecule, however, "suddenly becomes quite cytotoxic — it kills cells," he says. "We don't know the mechanism, but there is some interest in using it to fight cancer because it seems to act specifically on certain cells."

Sugars are also attached to proteins, cell surfaces and many other locations in biology, Thorson says. "By simplifying the attachment, we are improving the pharmacologist's toolbox. This study provides access to new reagents and offers a very convenient screening for new catalysts and/or new drugs, and for other things we haven't yet thought of. We believe this is going to open up a lot of doors."

Provided by University of Wisconsin-Madison (news : web)

Sweet insight: Discovery could speed drug development

 The surface of cells and many biologically active molecules are studded with sugar structures that are not used to store energy, but rather are involved in communication, immunity and inflammation. In a similar manner, sugars attached to drugs can enhance, change or neutralize their effects, says Jon Thorson, a professor of pharmaceutical sciences at the University of Wisconsin-Madison School of Pharmacy.

Thorson, an expert in the attachment and function of these sugars, says that understanding and controlling them has major potential for improving drugs, but that researchers have been stymied because many novel sugars are difficult to create and manipulate. "The chemistry of these sugars is difficult, so we have been working on methods to make it more user friendly," he says.

Now, in a study published online in Nature Chemical Biology on Aug. 21, Thorson, graduate student Richard Gantt and postdoctoral fellow Pauline Peltier-Pain have described a simple process to separate the sugars from a carrier molecule, then attach them to a drug or other chemical. The process also causes a color change only among those molecules that have accepted the sugar. The change in color should support a screening system that would easily select out transformed molecules for further testing. "One can put 1,000 drug varieties on a plate and tell by color how many of them have received the added sugar," Thorson says.

Attached sugars play a key role in pharmacy, says Thorson. Not only can they change the solubility of a compound, but "there are transporters in the body that specifically recognize certain sugars, and pharmaceutical companies have taken advantage of this to direct molecules toward specific tissue or cell types. If we can build a toolbox that allows us to make these molecules on demand, we can ask, 'What will sugar A do when it's attached to drug B?'"

And although the new study was focused more on an improved technique rather than the alteration of drugs, Thorson adds that it does describe the production of some "really interesting sugar-appended drugs: anti-virals, antibiotics, anti-cancer and anti-inflammatory drugs. Follow-up studies are currently under way to explore the potential of these analogs."

The new molecules included 11 variants of vancomycin, a powerful antibiotic, each distinguished by the nature and number of attached sugars.

The essence of the new process is its starting point: a molecule that changes the energy dynamics of the sugar-attachment reaction, Thorson says. "This is one of the first systematic studies of the equilibrium of the reaction, and it shows we can drive it forward or in reverse, depending on the molecule that we start with."

In a single test tube, the new technique is able to detach the sugar from its carrier and reattach it to the biological target molecule, Thorson says. "Sugars are involved a vast range of biology, but there are still many aspects that are not well understood about the impact of attaching and removing sugars, partly because of the difficulty of analyzing and accessing these species."

Making variants of potential and existing drugs is a standard practice for drug-makers, and a recently published study by Peltier-Pain and Thorson revealed that attaching a certain sugar to the anti-coagulant Warfarin destroys its anti-clotting ability. The transformed molecule, however, "suddenly becomes quite cytotoxic -- it kills cells," he says. "We don't know the mechanism, but there is some interest in using it to fight cancer because it seems to act specifically on certain cells."

Sugars are also attached to proteins, cell surfaces and many other locations in biology, Thorson says. "By simplifying the attachment, we are improving the pharmacologist's toolbox. This study provides access to new reagents and offers a very convenient screening for new catalysts and/or new drugs, and for other things we haven't yet thought of. We believe this is going to open up a lot of doors."

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by University of Wisconsin-Madison. The original article was written by David Tenenbaum.

Journal Reference:

Richard W Gantt, Pauline Peltier-Pain, William J Cournoyer, Jon S Thorson. Using simple donors to drive the equilibria of glycosyltransferase-catalyzed reactions. Nature Chemical Biology, 2011; DOI: 10.1038/nchembio.638

A flash of insight: Chemist uses lasers to see proteins at work

Enlarge

Binghamton University researcher Christof Grewer thinks he has an important brain transport protein -- glutamate transporter -- figured out and he's taking aim with lasers. Credit: Jonathan Cohen

Binghamton University researcher Christof Grewer thinks he has an important brain transport protein – glutamate transporter – figured out. And he's using a novel approach to spy on them by taking aim with lasers.

Grewer, a biophysical chemist, studies glutamate transport proteins, miniscule components of our brains that move glutamate among cells. Glutamate, an important molecule in cellular metabolism, is also a neurotransmitter. He explains his research on these tiny proteins in the brain using an analogy: imagine never having seen a car before and trying to determine what makes the vehicle run.

"We would be interested in seeing what happens when the car is moving, and we'd take pictures of that," he says. "We'd see the pistons moving, and that would be the beginning of understanding."

Scientists know the transport proteins are important, and they know they move glutamate in and out of cells through a sort of door in the cell wall, known as a glutamate transporter. But exactly how the proteins trigger those doors in the cell wall, and what makes them move glutamate to the inside or outside of a cell, is unknown.

Learning how those triggers function could have major implications for human health. For example, during a stroke, when blood and oxygen to the brain are restricted, brain cells release glutamate into the space surrounding them. That starts a toxic chain that can kill brain cells and harm certain brain functions. Knowing how the glutamate molecules are transported through cell walls could one day lead to drugs that help or halt the transport.

Grewer — one of perhaps two dozen researchers in the world who work on this problem — switches analogies as he continues describing the way these proteins move.

"Think about people being transported in an elevator in a tall building," he says. "So in order for that to work, the door of the elevator has to open, and then the person has to step into the elevator. And then the elevator brings you to a higher floor, and then the door has to open, and the person has to walk out."

In this case, glutamate molecules are the people. The elevator cars are the glutamate transporters. And the electricity and wires that move elevator doors are — well, that's what he's trying to figure out. Grewer's brainstorm was to create a method that uses lasers to trigger the transports' action. By controlling when the movement happens, he can document it. It all goes back to his analogy of photographing a car's pistons. Taking snapshots may illuminate how the transporters and glutamate molecules work together.

Grewer stumbled onto the glutamate transporters. When he was a graduate student in physical chemistry at Johann Wolfgang Goethe-University in Frankfurt, Germany, his research focused on chemistry and light. His introduction to biochemistry — and to glutamate receptors — came during a post-doctoral fellowship at
Cornell University.

"We were trying to activate these receptors on a very fast time scale," he says. "It's not that easy to do."

His background in chemistry and physics brought fresh insight to the lab. What if, he thought, a flash of light could help trigger the transport process? By timing the reactions, the researchers could better capture what happens during the glutamate transfer.

"They were so interesting to me that I just had to stay with them," Grewer says of glutamate transporters. "I thought, that is just the most amazing thing to study."

Most biochemical research on the brain focuses on possible cures and many researchers are experimenting with known drugs to judge their effect on brain function.

In most proteins, and in biology, researchers know what the genetic code and the DNA look like. The number of proteins in the body is also a known factor. But what's not unclear is how these proteins function. And that's where Grewer's work comes in. He has become a pioneer in the usage of lasers, which although used on other types of proteins, has not been used before in this area of study.

Provided by Binghamton University

A flash of insight: Chemist uses lasers to see proteins at work

Binghamton University researcher Christof Grewer thinks he has an important brain transport protein -- glutamate transporter -- figured out. And he's using a novel approach to spy on them by taking aim with lasers.

Grewer, a biophysical chemist, studies glutamate transport proteins, miniscule components of our brains that move glutamate among cells. Glutamate, an important molecule in cellular metabolism, is also a neurotransmitter. He explains his research on these tiny proteins in the brain using an analogy: imagine never having seen a car before and trying to determine what makes the vehicle run.

"We would be interested in seeing what happens when the car is moving, and we'd take pictures of that," he says. "We'd see the pistons moving, and that would be the beginning of understanding."

Scientists know the transport proteins are important, and they know they move glutamate in and out of cells through a sort of door in the cell wall, known as a glutamate transporter. But exactly how the proteins trigger those doors in the cell wall, and what makes them move glutamate to the inside or outside of a cell, is unknown.

Learning how those triggers function could have major implications for human health. For example, during a stroke, when blood and oxygen to the brain are restricted, brain cells release glutamate into the space surrounding them. That starts a toxic chain that can kill brain cells and harm certain brain functions. Knowing how the glutamate molecules are transported through cell walls could one day lead to drugs that help or halt the transport.

Grewer -- one of perhaps two dozen researchers in the world who work on this problem -- switches analogies as he continues describing the way these proteins move.

"Think about people being transported in an elevator in a tall building," he says. "So in order for that to work, the door of the elevator has to open, and then the person has to step into the elevator. And then the elevator brings you to a higher floor, and then the door has to open, and the person has to walk out."

In this case, glutamate molecules are the people. The elevator cars are the glutamate transporters. And the electricity and wires that move elevator doors are -- well, that's what he's trying to figure out. Grewer's brainstorm was to create a method that uses lasers to trigger the transports' action. By controlling when the movement happens, he can document it. It all goes back to his analogy of photographing a car's pistons. Taking snapshots may illuminate how the transporters and glutamate molecules work together.

Grewer stumbled onto the glutamate transporters. When he was a graduate student in physical chemistry at Johann Wolfgang Goethe-University in Frankfurt, Germany, his research focused on chemistry and light. His introduction to biochemistry -- and to glutamate receptors -- came during a post-doctoral fellowship at Cornell University.

"We were trying to activate these receptors on a very fast time scale," he says. "It's not that easy to do."

His background in chemistry and physics brought fresh insight to the lab. What if, he thought, a flash of light could help trigger the transport process? By timing the reactions, the researchers could better capture what happens during the glutamate transfer.

"They were so interesting to me that I just had to stay with them," Grewer says of glutamate transporters. "I thought, that is just the most amazing thing to study."

Most biochemical research on the brain focuses on possible cures and many researchers are experimenting with known drugs to judge their effect on brain function.

In most proteins, and in biology, researchers know what the genetic code and the DNA look like. The number of proteins in the body is also a known factor. But what's not unclear is how these proteins function. And that's where Grewer's work comes in. He has become a pioneer in the usage of lasers, which although used on other types of proteins, has not been used before in this area of study.

Story Source:

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

Patterns found in laboratory spark insight into nature and society

Irv Epstein's research is proving that patterns found in mathematical formulas and chemical reactions may be used to understand economics, how an epidemic might spread and the way animal populations survive in the natural world.

Irv Epstein is fascinated with patterns — how they show up in economics, in the coats of animals and within social systems.

“If you look for patterns in social systems, you see them in housing, segregation or in how an epidemic might spread,” says Epstein, the Henry F. Fischbach Professor of Chemistry. “In general, changes don’t occur smoothly, but in patterns that often have some regularity to them.”

While his research is done in the lab, it is proving that chemical reactions and mathematical formulas may also be used to understand how organisms move and the way animal populations survive in the natural world.

Epstein’s group studies oscillatory chemical reactions (systems in which concentrations of various chemical increase and decrease over time); cross-diffusion, spatial pattern formation, transformation of chemical into mechanical energy, dynamical systems and neurobiology. He is the former dean of arts and sciences and provost at Brandeis. He’s also a founder of the Science Posse, which brings underrepresented and economically disadvantaged students to Brandeis to study science.

Hired in 1971 to teach quantum mechanics, Epstein says his interest in oscillating reactions came about while working with some eager undergraduates who were looking for a summer project. Feeling that quantum mechanics would be a bit too complex for students who had just finished their freshman year, he recalled an article in the Journal of Chemical Education about oscillating chemical reactions and suggested the topic.

Little did he know the project would reroute his career.

“One of the students discovered something that contradicted a statement in the classic literature and figured out what was going on,” says Epstein. “We published a paper and I became more interested in this stuff, eventually changing fields completely.”

Epstein says non-linear dynamics and exotic reactions like oscillating chemical reactions are quite rare in chemistry but very important in biology, because every living system is full of reactions in which concentrations increase and decrease, typically on a daily cycle. Unraveling this phenomenon in chemistry is offering insights into pattern formation in other systems, such as human and animal populations.? To better understand diffusion, cross-diffusion and oscillatory chemical reactions, Epstein revisits a science demo popular with the elementary school set: The glass of water and drop of food coloring.
Diffusion is the phenomenon by which a species spreads out from a concentrated region to a less concentrated region. When a drop of red food coloring is placed in a glass of water, the food coloring disperses over time, resulting in a uniform pink glass of colored water. The process by which the color spreads is diffusion.

Cross-diffusion is a process in which two species are spreading- for example, if you have both a red drop and a blue drop of food coloring; the “cross” aspect means that the distribution of one color affects the diffusion of the other.

“Chemists and physicists have largely ignored cross-diffusion,” says Epstein. “When you study diffusion in an introductory chemistry or physics course, the standard treatment completely ignores the possibility that if there are two different chemicals present one might influence the diffusion of the other.”

Using his theories, Epstein is creating mathematical models to use in the context of biological, ecological and social systems.

“Instead of having blue molecules and red molecules, maybe you have populations of two different ethnic groups that either like to be near each other or prefer to avoid each other,” says Epstein. “This might affect population patterns in a city or region.”

While he’s not expecting urban planners to track him down this year, his research is gaining momentum.

In ecology, Epstein says, one can create models to describe a predator-prey system.

“Suppose I have foxes and rabbits,” says Epstein. “If the rabbits are by themselves, they’ll distribute evenly, assuming that the food supply is evenly distributed. But if I introduce foxes into the system, then the foxes will eat the rabbits and the rabbits will tend to move away from high concentrations of foxes.” You can actually [design] a mathematical model that describes the processes by which rabbits eat grass and multiply, foxes eat rabbits and multiply and the two species move around.”

While many of the exotic reactions that Epstein examines touch on oscillation and transience, Epstein himself is an example of steadfastness.

Epstein has spent this year at Harvard as Radcliffe Institute Fellow, but he has literally spent his adult life at Brandeis. He arrived in 1971 during the bitter end of the Vietnam War, experienced the ‘80s with the explosion of the space shuttle Challenger and the discovery of AIDS, the ‘90s with the release of Nelson Mandela, the end of the Cold War and the dawn of the 21st century, where smart phones and social media have changed the way people live their lives.
As Epstein points out, the lab facilities at Brandeis have evolved as well.

“When I started at Brandeis,” he says, “ I had only a small office and no labs. As I shifted my efforts from theory to experiment, generous colleagues offered to share lab space with me, and I eventually inherited labs of my own when they retired, but the space was less than ideal.”

Two years ago his research team moved to the newly constructed Shapiro Science Center, where, for the first time, Epstein says, they can control key variables such as room temperature and lighting levels without having to resort to Rube Goldberg-like “fixes.”

A native of Queens, N.Y., Epstein was an only child. His father was a locksmith born in Russia, his mother a school librarian. He earned a B.A. in chemistry and physics, an M.A. in chemistry and a Ph.D. in chemical physics from Harvard University and a diploma in advanced mathematics as a Marshall Scholar at the University of Oxford. After a NATO post-doctoral fellowship at the University of Cambridge, he moved from England to New England, accepting a position at Brandeis.

Twenty-one years later, Epstein was made dean of arts and sciences, moving up to provost in 1994 when the incumbent provost, Jehuda Reinharz, became Brandeis’ seventh president.

Robin Feuer Miller, professor of Russian literature who served as dean of arts and sciences from 1994-2000, worked closely with Epstein during his seven- year term as provost.

“He is, quite simply, one of the smartest people I know,” says Miller. “But what I perhaps valued most about working with him was his ability to change his mind” after making an effort to understand another side.
On the occasions when they disagreed, Miller said, they were always able to talk things through and come to an amicable decision.

Perhaps it’s this passion for people and progress that played into Epstein’s success in garnering a million-dollar grant in 2006 from the Howard Hughes Medical Institute (HHMI), the nation’s largest private funder of science education, to start the first Science Posse, a program at Brandeis created to attract and retain talented, underrepresented students in college-level science.

“If you look at the statistics, the state of American science, we are falling behind,? says Epstein. “More than half of the graduate students in chemistry, math and physics are from other countries. And if you look even more closely, underrepresented minorities are even more underrepresented in the sciences.”

In 2010, the foundation awarded an additional $600,000 to further develop the program. The Science Posse is an extension of the successful Posse Foundation, a liberal arts program founded in 1989 by Brandeis alum Deborah Bial ‘87, which carefully selects and trains a group or “posse” of students who act as a support system for each other.

Though the students don’t know each other when they’re chosen, between the time that they’re selected in December and when they arrive on campus in September, they will have spent 3-4 hours a week together, bonding and learning skills from time management to persuasive writing.

“Irv has vision,” says assistant biology professor Melissa Kosinski-Collins who runs the academic side of the Science Posse as well as the summer boot camp. “He genuinely cares about our scholars and makes it his goal to be there when they need him.”

Jerry Saunders II ‘11 is a member of the Science Posse. He said that working in Epstein’s lab was one of the highlights of his undergraduate career.

“Dr. Epstein is a real-time celebrity whose example constantly challenges me to always strive for more,” says Saunders. “Despite his many successes he remains interested in the work you are doing and what you hope to accomplish. Furthermore, he is more than willing to assist you in that path. He is never too busy to lend guidance.”

Eve Marder, head of division of science and the Victor and Gwendolyn Beinfield Professor of Neuroscience, got to know Epstein in the late 1980s when the pair collaborated on building a semi-realistic model of a neuro-oscilator; in other words, they developed mathematical models used to research several kinds of neurons that are studied in Marder’s lab.

“He was doing the theory and we went back and forth discussing the biology,” says Marder. The two also wrote a grant together.

“Irv has got to be the fastest writer and fastest and best editor that I’ve ever worked with,” says Marder. “He’s astronomically quick. I think that’s part of the reason that he’s been so successful and productive.”

More information: http://pubs.acs.or … eda8/current

Provided by Brandeis University (news : web)

New insight into how 'tidying up' enzymes work

A new discovery about how molecules are broken down by the body, which will help pharmaceutical chemists design better drugs, has been made by researchers at the University of Bristol.

Working with Professor Jeremy Harvey and Professor Adrian Mulholland of Bristol's School of Chemistry, Dr Julianna Olah, an EU Marie Curie Fellow in Bristol at the time, studied a class of enzymes – cytochromes P450 – which play an important role in removing drug molecules from the body.

When a tablet of medicine is taken, the active molecules get absorbed into the bloodstream through the gut and make their way around the body, including to the cells in which they are intended to act; however, it's important they don't stay in the body forever. Enzymes (biological catalysts) help break them down to facilitate excretion.

The cytochromes P450 are a very important class of these 'tidying up' enzymes which have evolved to deal with all 'foreign' compounds that do not get broken down as part of normal metabolism (that is, any compounds which are not proteins, carbohydrates or lipids).

Mainly situated in the liver, the P450 enzymes help remove drug molecules by adding oxygen to them. This process usually works smoothly, but for some molecules, it can lead to oxygenated variants that are toxic. Other molecules are also able to interfere with the normal function of the P450 enzymes.

For these reasons, it is important to be able to understand how a given new molecule, considered for use as a medicine, will react with these enzymes. The Bristol researchers aimed to provide this understanding by modeling the reaction mechanism for interaction between one specific drug (dextromethorphan, a component of some cough syrups) and one P450 variant.

Professor Jeremy Harvey said: "Our calculations showed that the outcome of the oxygen transfer process (that is, which part of dextromethorphan oxygen gets added to) is affected by three factors.

"The first is the way in which the molecule fits into the enzyme ('docking'). The second is the intrinsic ability of each part of the molecule to accept oxygen. The third is how much each competing oxygen-delivery process is compatible with the shape of the enzyme pocket where the reaction occurs.

"While these first two factors were already known, the third was not. This discovery can help pharmaceutical chemists design new drug molecules with a better understanding of how they will be broken down in the body."

Provided by University of Bristol (news : web)

Neutron analysis yields insight into bacteria for solar energy

Structural studies of some of nature's most efficient light-harvesting systems are lighting the way for new generations of biologically inspired solar cell devices.

Researchers from Washington University in St. Louis and the Department of Energy's Oak Ridge National Laboratory used small-angle neutron scattering to analyze the structure of chlorosomes in green photosynthetic bacteria. Chlorosomes are efficient at collecting sunlight for conversion to energy, even in low-light and extreme environments.

"It's one of the most efficient light harvesting antenna complexes found in nature," said co-author and research scientist Volker Urban of ORNL's Center for Structural Molecular Biology, or CSMB.

Neutron analysis performed at the CSMB's Bio-SANS instrument at the High Flux Isotope Reactor allowed the team to examine chlorosome structure under a range of thermal and ionic conditions.

"We found that their structure changed very little under all these conditions, which shows them to be very stable," Urban said. "This is important for potential biohybrid applications -- if you wanted to use them to harvest light in synthetic materials like a hybrid solar cell, for example."

The size, shape and organization of light-harvesting complexes such as chlorosomes are critical factors in electron transfer to semiconductor electrodes in solar devices. Understanding how chlorosomes function in nature could help scientists mimic the chlorosome's efficiency to create robust biohybrid or bio-inspired solar cells.

"What's so amazing about the chlorosome is that this large and complicated assembly is able to capture light effectively across a large area and then funnel the light to the reaction center without losing it along the way," Urban said. "Why this works so well in chlorosomes is not well understood at all."

"We're trying to find out general principles that are important for capturing, harvesting and transporting light efficiently and see how nature has solved that," Urban said.

Small-angle neutron scattering enabled the team to clearly observe the complicated biological systems at a nanoscale level without damaging the samples.

"With neutrons, you have an advantage that you get a very sharp contrast between these two phases, the chlorosome and the deuterated buffer. This gives you something like a clear black and white image," Urban said.

The team, led by Robert Blankenship of Washington University, published its findings in the journal Langmuir. The research was supported through the Photosynthetic Antenna Research Center, an Energy Frontier Research Center funded by DOE's Office of Science. Both HFIR and the Bio-SANS facility at ORNL's Center for Structural Molecular Biology are also supported by DOE's Office of Science.

ORNL is managed by UT-Battelle for the Department of Energy's Office of Science.

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by DOE/Oak Ridge National Laboratory.

Journal Reference:

Kuo-Hsiang Tang, Liying Zhu, Volker S. Urban, Aaron M. Collins, Pratim Biswas, Robert E. Blankenship. Temperature and Ionic Strength Effects on the Chlorosome Light-Harvesting Antenna Complex. Langmuir, 2011; 110315121146005 DOI: 10.1021/la104532b