A 'wild card' in your genes

Rahul Kohli and colleagues focus on cytosine, one of the four chemical "bases" that comprise the alphabet that the genetic material DNA uses to spell out everything from hair and eye color to risk of certain diseases. But far from just storing information, cytosine has acquired a number of other functions that give it a claim to being the genome's wild card. "In poker, the rules of the game can occasionally change," they note in the article. "Adding a 'wild card' to the mix introduces a new degree of variety and presents opportunities for a skilled player to steal the pot. Given that evolution is governed by the same principles of risk and reward that are common to a poker game, it is perhaps not surprising that a genomic 'wild card' has an integral role in biology."

They discuss the many faces of cytosine that make it such a game-changer and the biological processes that help to change its identity. Removing something called an amine group from cytosine, for instance, allows the immune system to recognize and destroy foreign invaders such as viruses. Adding so-called "methyl groups" on cytosines acts as on/off switches for genes. The authors say that these many faces of cytosine allow it to play various roles and give it true "wild card" status.

More information: The Curious Chemical Biology of Cytosine: Deamination, Methylation,and Oxidation as Modulators of Genomic Potential, ACS Chem. Biol., Article ASAP. DOI: 10.1021/cb2002895

Abstract
A multitude of functions have evolved around cytosine within DNA, endowing the base with physiological significance beyond simple information storage. This versatility arises from enzymes that chemically modify cytosine to expand the potential of the genome. Some modifications alter coding sequences, such as deamination of cytosine by AID/APOBEC enzymes to generate immunologic or virologic diversity. Other modifications are critical to epigenetic control, altering gene expression or cellular identity. Of these, cytosine methylation is well understood, in contrast to recently discovered modifications, such as oxidation by TET enzymes to 5-hydroxymethylcytosine. Further complexity results from cytosine demethylation, an enigmatic process that impacts cellular pluripotency. Recent insights help us to propose an integrated DNA demethylation model, accounting for contributions from cytosine oxidation, deamination, and base excision repair. Taken together, this rich medley of alterations renders cytosine a genomic “wild card”, whose context-dependent functions make the base far more than a static letter in the code of life.

Provided by American Chemical Society (news : web)

Supercomputer reveals new details behind drug-processing protein model

Jerome Baudry and Yinglong Miao, who are jointly affiliated with ORNL and the University of Tennessee, have performed simulations to observe the motions of water molecules in a class of enzymes called P450s. Certain types of P450 are responsible for processing a large fraction of drugs taken by humans.

The supercomputer simulations were designed to help interpret ongoing neutron experiments.

"We simulated what happens in this enzyme over a time scale of 0.3 microseconds, which sounds very fast, but from a scientific point of view, it's a relatively long time," Baudry said. "A lot of things happen at this scale that had never been seen before. It's a computational tour de force to be able to follow that many water molecules for that long."

The team's study of the water molecules' movements contributes to a broader understanding of drug processing by P450 enzymes. Because some populations have a slightly different version of the enzymes, scientists hypothesize that mutations could partially explain why people respond differently to the same drug. One possibility is that the mutations might shut down the channels that bring water molecules in and out of the enzyme's active site, where the chemical modification of drugs takes place. This could be investigated by using the computational tools developed for this research.

By simulating how water molecules move in and out of the protein's centrally located active site, the team clarified an apparent contradiction between experimental evidence and theory that had previously puzzled researchers. X-ray crystallography, which provides a static snapshot of the protein, had shown only six water molecules present in the active site, whereas experimental observations indicated a higher number of water molecules would be present in the enzyme.

"We found that even though there can be many water molecules -- up to 12 at a given time that get in and out very quickly -- if you look at the average, those water molecules prefer to be at a certain location that corresponds to what you see in the crystal structure," Miao said. "It's a very dynamic hydration process that we are exploring with a combination of neutron scattering experiments and simulation."

The simulation research is published in Biophysical Journal as "Active-Site Hydration and Water Diffusion in Cytochrome P450cam: A Highly Dynamic Process."

Provided by Oak Ridge National Laboratory (news : web)

NMR used to determine whether gold nanoparticles exhibit 'handedness'

 Carnegie Mellon University's Roberto R. Gil and Rongchao Jin have successfully used NMR to analyze the structure of infinitesimal gold nanoparticles, which could advance the development and use of the tiny particles in drug development.

Their approach offers a significant advantage over routine methods for analyzing gold nanoparticles because it can determine whether the nanoparticles exist in a both right-handed and left-handed configuration, a phenomenon called chirality. Determining a nanoparticle's chirality is an important step toward developing them as chiral catalysts -- tools that are highly sought-after by the pharmaceutical industry. Their results are published online at ACS Nano.

Many drugs on the market today contain at least one molecule that is chiral. Often only one of the configurations, or isomers, is effective in the body. In some cases, the other isomer may even be harmful. A striking example is the drug thalidomide, which consisted of two isomers: one of which helped pregnant women control nausea while the other caused damage to the developing fetus. In an effort to create safer, more effective drugs, drug manufacturers are looking for ways to produce purer substances that contain only the left- or right-handed isomer.

Huifeng Qian, a fourth-year graduate student working with Jin, created a gold nanoparticle that has the potential to catalyze chemical reactions that will produce one isomer rather than the other. The nanoparticle is composed of precisely 38 gold atoms and measures a mere 1.4 nanometers. Qian worked diligently for nearly a year to grow the nanoparticles into high-quality crystals so that he could study their structure using x-ray crystallography.

"Growing a pure crystal from nanoparticles is very challenging, and you may not even be able to get a crystal at all," said Jin, an assistant professor of chemistry in CMU's Mellon College of Science. "In the nanoparticle community, the crystal structures of only three nanoparticles have been reported."

In Jin's case, x-ray crystallography revealed that the gold nanoparticle is chiral. Chemists typically probe the internal chiral structure of gold nanoparticles using a technique called circular dichoism spectroscopy. When pure chiral molecules are exposed to circularly polarized light, each isomer absorbs the light differently, resulting in a unique -- and of opposite sign -- spectrum for each isomer. The process of creating the gold nanoparticles, however, often results in a 50/50 mix of each isomer, known as racemates.

"Because the spectrum is of opposite sign for each isomer, they cancel each other out and the net optical response is zero. This makes circular dichoism (CD) spectroscopy useless when it comes to determining the chirality of gold nanoparticles in 50/50 mixtures," said Gil, associate research professor of chemistry and director of the Department of Chemistry's NMR Facility.

Since Jin couldn't use circular dichoism spectroscopy, Gil was able to use NMR to help Jin distinguish between his gold nanoparticles' left- and right-handed isomers.

NMR spectroscopy takes advantage of the physical phenomenon wherein some nuclei wobble and spin like tops, emitting and absorbing a radio frequency signal in a magnetic field. By observing the behavior of these spinning nuclei, scientists can piece together the chemical structure of the compound.

In 1957, scientists observed that the hydrogen atoms of a freely rotating methylene (CH2) group produced two different frequencies if they were close to a chiral center. Jin's gold nanoparticles, which have a chiral core, are cushioned by several chemical groups, including freely rotating methylene groups. Gil reasoned that the nanoparticles' chiral core should induce the methylene group's two hydrogen atoms to give off different frequencies, a phenomenon known as diastereotopicity.

Gil and Jin compared the NMR signal from the hydrogen atoms in a non-chiral gold nanoparticle with the NMR signal from the hydrogen atoms in chiral gold nanoparticle. The non-chiral nanoparticle's NMR spectrum did not reveal any differences, but the chiral nanoparticle's NMR spectrum revealed two different hydrogen signals, providing a simple and efficient way of telling whether the particle is chiral or not, even for a 50/50 mixture of isomers.

"NMR is an alternative -- and very efficient -- method for providing useful information about how the atoms in nanoparticles form the molecular structure. Because NMR can determine chirality in some cases, it can readily be used to determine the purity of a nanoparticle mixture," Jin said.

In current work, Jin and Qian are striving to turn their 50/50 mixture of right- and left-handed isomers into a pure solution of one or the other.

Story Source:

The above story is reprinted from materials provided by Carnegie Mellon University. The original article was written by Jocelyn Duffy.

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

Journal Reference:

Huifeng Qian, Manzhou Zhu, Chakicherla Gayathri, Roberto R. Gil, Rongchao Jin. Chirality in Gold Nanoclusters Probed by NMR Spectroscopy. ACS Nano, 2011; 5 (11): 8935 DOI: 10.1021/nn203113j

World's smallest steam engine: Heat engine measuring only a few micrometers works as well as its larger counterpart, although it sputters

 What would be a case for the repair shop for a car engine is completely normal for a micro engine. If it sputters, this is caused by the thermal motions of the smallest particles, which interfere with its running. Researchers at the University of Stuttgart and the Stuttgart-based Max Planck Institute for Intelligent Systems have now observed this with a heat engine on the micrometre scale. They have also determined that the machine does actually perform work, all things considered. Although this cannot be used as yet, the experiment carried out by the researchers in Stuttgart shows that an engine does basically work, even if it is on the microscale. This means that there is nothing, in principle, to prevent the construction of highly efficient, small heat engines.

A technology which works on a large scale can cause unexpected problems on a small one. And these can be of a fundamental nature. This is because different laws prevail in the micro- and the macroworld. Despite the different laws, some physical processes are surprisingly similar on both large and small scales. Clemens Bechinger, Professor at the University of Stuttgart and Fellow of the Max Planck Institute for Intelligent Systems, and his colleague Valentin Blickle have now observed one of these similarities.

"We've developed the world's smallest steam engine, or to be more precise the smallest Stirling engine, and found that the machine really does perform work," says Clemens Bechinger. "This was not necessarily to be expected, because the machine is so small that its motion is hindered by microscopic processes which are of no consequence in the macroworld." The disturbances cause the micromachine to run rough and, in a sense, sputter.

The laws of the microworld dictated that the researchers were not able to construct the tiny engine according to the blueprint of a normal-sized one. In the heat engine invented almost 200 years ago by Robert Stirling, a gas-filled cylinder is periodically heated and cooled so that the gas expands and contracts. This makes a piston execute a motion with which it can drive a wheel, for example.

"We successfully decreased the size of the essential parts of a heat engine, such as the working gas and piston, to only a few micrometres and then assembled them to a machine," says Valentin Blickle. The working gas in the Stuttgart-based experiment thus no longer consists of countless molecules, but of only one individual plastic bead measuring a mere three micrometres (one micrometre corresponds to one thousandth of a millimetre) which floats in water. Since the colloid particle is around 10,000 times larger than an atom, researchers can observe its motion directly in a microscope.

The physicists replaced the piston, which moves periodically up and down in a cylinder, by a focused laser beam whose intensity is periodically varied. The optical forces of the laser limit the motion of the plastic particle to a greater and a lesser degree, like the compression and expansion of the gas in the cylinder of a large heat engine. The particle then does work on the optical laser field. In order for the contributions to the work not to cancel each other out during compression and expansion, these must take place at different temperatures. This is done by heating the system from the outside during the expansion process, just like the boiler of a steam engine. The researchers replaced the coal fire of an old-fashioned steam engine with a further laser beam that heats the water suddenly, but also lets it cool down as soon as it is switched off.

The fact that the Stuttgart machine runs rough is down to the water molecules which surround the plastic bead. The water molecules are in constant motion due to their temperature and continually collide with the microparticle. In these random collisions, the plastic particle constantly exchanges energy with its surroundings on the same order of magnitude as the micromachine converts energy into work. "This effect means that the amount of energy gained varies greatly from cycle to cycle, and even brings the machine to a standstill in the extreme case," explains Valentin Blickle. Since macroscopic machines convert around 20 orders of magnitude more energy, the tiny collision energies of the smallest particles in them are not important.

The physicists are all the more astonished that the machine converts as much energy per cycle on average despite the varying power, and even runs with the same efficiency as its macroscopic counterpart under full load. "Our experiments provide us with an initial insight into the energy balance of a heat engine operating in microscopic dimensions. Although our machine does not provide any useful work as yet, there are no thermodynamic obstacles, in principle, which prohibit this in small dimensions," says Clemens Bechinger. This is surely good news for the design of reliable, highly efficient micromachines.

The above story is reprinted from materials provided by Max-Planck-Gesellschaft.

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

Journal Reference:

Valentin Blickle and Clemens Bechinger. Realization of a micrometre-sized stochastic heat engine. Nature Physics, 11 December 2011 DOI: 10.1038/NPHYS2163

'Fool's gold' aids discovery of new options for cheap, benign solar energy

 Pyrite, better known as "fool's gold," was familiar to the ancient Romans and has fooled prospectors for centuries -- but has now helped researchers at Oregon State University discover related compounds that offer new, cheap and promising options for solar energy.

These new compounds, unlike some solar cell materials made from rare, expensive or toxic elements, would be benign and could be processed from some of the most abundant elements on Earth. Findings on them have been published in Advanced Energy Materials, a professional journal.

Iron pyrite itself has little value as a future solar energy compound, the scientists say, just as the brassy, yellow-toned mineral holds no value compared to the precious metal it resembles. But for more than 25 years it was known to have some desirable qualities that made it of interest for solar energy, and that spurred the recent research.

The results have been anything but foolish.

"We've known for a long time that pyrite was interesting for its solar properties, but that it didn't actually work," said Douglas Keszler, a distinguished professor of chemistry at OSU. "We didn't really know why, so we decided to take another look at it. In this process we've discovered some different materials that are similar to pyrite, with most of the advantages but none of the problems.

"There's still work to do in integrating these materials into actual solar cells," Keszler said. "But fundamentally, it's very promising. This is a completely new insight we got from studying fool's gold."

Pyrite was of interest early in the solar energy era because it had an enormous capacity to absorb solar energy, was abundant, and could be used in layers 2,000 times thinner than some of its competitors, such as silicon. However, it didn't effectively convert the solar energy into electricity.

In the new study, the researchers found out why. In the process of creating solar cells, which takes a substantial amount of heat, pyrite starts to decompose and forms products that prevent the creation of electricity.

Based on their new understanding of exactly what the problem was, the research team then sought and found compounds that had the same capabilities of pyrite but didn't decompose. One of them was iron silicon sulfide.

"Iron is about the cheapest element in the world to extract from nature, silicon is second, and sulfur is virtually free," Keszler said. "These compounds would be stable, safe, and would not decompose. There's nothing here that looks like a show-stopper in the creation of a new class of solar energy materials."

Work to continue the development of the materials and find even better ones in the same class will continue at the National Renewable Energy Laboratory in Colorado, which collaborated on this research.

The work was done at the Center for Inverse Design, a collaborative initiative of the College of Science and College of Engineering at OSU, formed two years ago with a $3 million grant from the U.S. Department of Energy. It was one of the new Energy Frontier Research Centers set up through a national, $777 million federal program to identify energy solutions for the future.

The OSU program is different from traditional science, in which the process often is to discover something and then look for a possible application. In this center, researchers start with an idea of what they want and then try to find the kind of materials, atomic structure or even construction methods it would take to achieve it.

Finding cheap, environmentally benign and more efficient materials for solar energy is necessary for the future growth of the industry, researchers said.

"The beauty of a material such as this is that it is abundant, would not cost much and might be able to produce high-efficiency solar cells," Keszler said. "That's just what we need for more broad use of solar energy."

Story Source:

The above story is reprinted from materials provided by Oregon State University.

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

Journal Reference:

Liping Yu, Stephan Lany, Robert Kykyneshi, Vorranutch Jieratum, Ram Ravichandran, Brian Pelatt, Emmeline Altschul, Heather A. S. Platt, John F. Wager, Douglas A. Keszler, Alex Zunger. Iron Chalcogenide Photovoltaic Absorbers. Advanced Energy Materials, 2011; 1 (5): 748 DOI: 10.1002/aenm.201100351