The readers of Antony's blog know enough about the problem. And many in the QSAR community know it too (and many other do not). Chemical structure data is noisy. I haven't recently created a new local data set for analysis, so I have not taken time to blog about it much, but the ambiguity in chemical databases is enormous. Just yesterday, Antony and I had a good discussion about tautomers and in particular how things are linked together.
If we are in the field of property prediction, knowing what tautomer to calculate descriptors for is crucial. Not that we actually have easy access to experimental data showing what the important tautomer is for our end-point (predicted property), but at least we can track what tautomer we modeled with. Has everyone ever asked you to add units to experimental values? Like "the temperarature was 279 degrees; Celsius or Kelvin??" Well, this is the exact same thing. If your QSAR model training report does not include that information, you are doing it wrong. (/me ducks)
So, why does it in fact matter? It matter simply because calculated properties are different. Backing up to the ChemSpider example in my question about InChIs with the fixed-hydrogen layer I noted that (like in many other databases) the synonyms seems to include IUPAC names for at least two tautomers. However, while the ChemSpider is, in fact, for the tautomer-independent structure (using the InChI mobile hydrogen layer; and keep in mind that the InChI uses only a limited amount of heuristic rules for identifying tautomers, making it not detect all 40 tautomers of warfarin), the 2D diagram, the 3D model, and the calculated properties reflect only one tautomer.
And calculated properties are exactly the input in QSAR's statistical modeling. It is interesting to realize that the differences in calculated molecular descriptors can vary both minimally, or not at all, as drastically. Very drastically, in fact. The recent paper by Porter (doi:10.1007/s10822-010-9335-7) shows the 40 warfarin tautomers, and discusses a few properties, such as the pKa. The experimental pKa of warfarin is around 5. Now, the paper reports calculated pKa values for a variety of software products (AMBIT is unfortunately missing). First of all, it shows that the various tools differ, which is to be expected. But that variance is neglectable when compared by the effect of picking the wrong tautomer. I was impressed by the range of predicted values for the various tautomers. I ranged from about 5 to 12, throughout all tools. That means warfarin is predicted to be mildly acidic (some tools predict pKa's down to 2.5) to very basic! No way your statistical modeling will understand that!
And this is why Open Data is so important in chemistry. So, the next time Joe (Organic) Chemist bitches about computers and cheminformatics, tell him it is his own fault: he should have released his data out in the Open.
Anyway. Tautomerism was a curation issue in the first(!!!) entry I was curating. The sixth had the more well-known problem, I think. I may be blind, but I would say this drug has a stereocenter:
But not of the databases I checked so far (including ChemSpider) defines the stereochemistry! I thought we settled that some decades ago? Stereochemistry of drugs matter. What is going on here? I guess I have to browse some primary literature and access some experimental data today then. If I can afford it.
Porter, W. (2010). Warfarin: history, tautomerism and activity Journal of Computer-Aided Molecular Design, 24 (6-7), 553-573 DOI: 10.1007/s10822-010-9335-7... Read more »
Trying to capture the movement of a colony of leaf-cutter ants in a single photo is nearly impossible in my (amateur) experience. The queues of ants follow a worn-down trail in the ground that they themselves made with the impact of their little ant feet. There are ants moving in both directions, between the food [...]... Read more »
Currie, C., Scott, J., Summerbell, R., & Malloch, D. (1999) Fungus-growing ants use antibiotic-producing bacteria to control garden parasites. Nature, 398(6729), 701-704. DOI: 10.1038/19519
Schoenian, I., Spiteller, M., Ghaste, M., Wirth, R., Herz, H., & Spiteller, D. (2011) Chemical basis of the synergism and antagonism in microbial communities in the nests of leaf-cutting ants. Proceedings of the National Academy of Sciences, 108(5), 1955-1960. DOI: 10.1073/pnas.1008441108
New research from Japan brings good news: dogs can be almost as accurate as a colonoscopy exam.In patients with colorectal cancer (CRC) and controls, the sensitivity of canine scent detection of breath samples compared with conventional diagnosis by colonoscopy was 0.91 and the specificity was 0.99. The sensitivity of canine scent detection of watery stool samples was 0.97 and the specificity was 0.99. The accuracy of canine scent detection was high even for early cancer. Canine scent detection was not confounded by current smoking, benign colorectal disease or inflammatory disease. As simple as that: exhaling 100-200 ml into a breath sampling bag and storing it in a Ziploc bag at 4°C until a trained dog has a change to sniff it can be enough for diagnostics. Just one breath sample! And it was almost as good as a watery stool sample obtained during colonoscopy or this joyous examination itself.There have been many research studies that dogs, rats and even moth can detect scents pertaining to human disease. Ordinary household dogs can be trained to distinguish breath odors (McCulloch et al 2006). For some cancers, sensitivity can be as high as 100% (Horvath et al 2008). Unfortunately, sophisticated mass-spectrometry, gas chromatography and software tools interpreting the signals are still not as good as our four-legged friends that are never getting lost in the noise of disease-unrelated flavors.But we are getting better in identifying specific chemicals responsible for various conditions - from alkanes - such as pentane in breath of IBD patients and polystyrene foam or aromatic components of petroleum in cancer breath to blends of fatty acids like oleic and linoleic acids forming the smell of death. Perhaps pet rats will find their use as pocket doctors before men-made sensors are developed to cope with infections, medical conditions, even fear and anxiety that also have a distinctive odor signature. In any case, Dr. Sonoda and his colleagues bring us a reassuring word that not every frequent visitor to the GI doctor's office will have to experience the joys of a colonoscopy. Sonoda H, Kohnoe S, Yamazato T, Satoh Y, Morizono G, Shikata K, Morita M, Watanabe A, Morita M, Kakeji Y, Inoue F, & Maehara Y (2011). Colorectal cancer screening with odour material by canine scent detection. Gut PMID: 21282130Other published literature on olfactory signatures in gastrointestinal disease:Cheu HW, Brown DR, Rowe MI (1989) Breath hydrogen excretion as a screening test for the early diagnosis of necrotizing enterocolitis. Am J Dis Child 1989;143:156–9.Pelli MA, Trovarelli G,, Capodicasa E, Breath alkanes determination in ulcerative colitis and Crohn's disease. Dis Colon Rectum 1999;42:71–6.Pelton NS, Tivey DR, Howarth GS, A novel breath test for the non-invasive assessment of small intestinal mucosal injury following methotrexate administration in the rat. Scand J Gastroenterol 2004;9:1015–16. Tibble JA, Sigthorsson G, Foster R, Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology 2002;123:450–60.... Read more »
Sonoda H, Kohnoe S, Yamazato T, Satoh Y, Morizono G, Shikata K, Morita M, Watanabe A, Morita M, Kakeji Y.... (2011) Colorectal cancer screening with odour material by canine scent detection. Gut. PMID: 21282130
Brief introduction to the new research identifying how red blood cells run their circadian rhythm without transcription & translation.... Read more »
The shadow of symmetry haunts physics. Symmetry is invoked to understand nature concisely, but broken symmetry is invoked to understand nature completely. Physics is filled with examples of shattered symmetries: there is more matter than antimatter, neutrinos only come in the left handed spin flavor, and quantum processes break symmetries constantly, but nature also violates symmetry in chemistry and biology in a very clever manner. Chemistry and biology are subjects I do no normally touch upon, but I am intrigued by the curious circumstance of life on Earth: many molecules are not superimposable upon their mirror images, a property called chirality, and life on Earth has a preference for these chiral mirror configurations. Physics and life is inherently asymmetric.That something is not identical to its mirror image is a property known as chirality. Hands (etymologically the word chirality is derived from the Greek word for hand), spiral galaxies, and the DNA helix are all examples of chiral objects. In particle physics chirality is actually an abstract notion defined by transformations of the particle with respect to their right of left handed representation in the Poincaré group. In chemistry chirality is well described by analogy to your hands wherein left and right hands cannot be superposed on each other even though the fingers are the same and match up. This article is an exploration of chirality in biochemistry. I want to ask what makes life chiral, why is life chiral, and how did life become chiral. In order to supplement my limited knowledge of the subject I interviewed a world expert and author of over twenty papers on the subject, Robert Compton, who I must give a deep thanks to for being willing to answer my silly questions.It is important to accept that the concept of symmetry is tinted by the human notion of harmonious or aesthetically pleasing forms, but the strict mathematical interpretation of symmetry relies upon metrics of geometry. To this end many seemingly symmetric forms in the living natural world are actually examples of broken symmetries: spiral tree trunks, the human form, and sea shells (which generally only coil in one particular direction according to species). The remarkable thing is that this macro asymmetry can be traced back to a micro asymmetry in the chemistry of life. The arrangement of atoms in a molecule defines the function of that molecule, but even molecules with the same chemical configuration can behave differently as in the case of chiral molecules which are like mirror images of the same molecule that come in 'left' and 'right' handed forms. The great asymmetry of life is that all living organisms on Earth almost exclusively utilize the left handed (or levorotatory) configuration for amino acids and the right handed (or dextrorotatory) configuration for sugars belonging to DNA or RNA.Perhaps it is trivial or obvious that life is chiral when looking at the nautilus, but this obvious chirality is a macroscopic feature which belies the fine arrangement of atoms which defines the chirality of biomolecules.Different structural forms of compounds with the same molecular formula are known as isomers to chemists. A stereoisomer is an isomeric molecule which has the identical constitution and sequence of bonded atoms, but has a different three-dimensional geometry in space. An enantiomer is one specific steroisomer of the two possible mirror images that are non-superposable. The dominance of the left handed chiral enantiomer in biology is a massive blow to the idea that nature is perfectly symmetric and is an unsolved mystery as to why nature is this way.Many molecules are chiral, however because molecules are constantly vibrating the instantaneous structure of a molecule may lack the exact structure or symmetry seen in an ideal model. Regardless, enantiomers have identical chemical properties except when they react with other molecules which are also enantiomeric in which case chiral forces yield a difference in behavior. Further, and perhaps more important for biology, particularly astrobiology, is that enantiomers have identical physical properties except with respect to the way they interact with plane-polarized or circularly polarized light or other chiral compounds. A pure enantiomer compound will rotate the plane of a monochromatic plane-polarized light by a certain angle in one direction, say clockwise, while the other enantiomer form of the compound will rotate the light by an equal amount in the opposite direction. Things that rotate light are said to be optically active. Measurements with a polarimeter allow chemists to determine if a compound is chiral or not. Polarization of light by organic compounds was discovered in 1815 by the French physicist and chemist Jean-Baptiste Biot. He found that organically produced chemical solutions consistently rotated plane polarized light, but laboratory synthesized chemicals did not reproduce the rotation. Beyond conjectures he had no explanation for the phenomena.Years later Louis Pasteur preformed a similar experiment with tartaric acid produced from grapes and tartaric acid synthesized in the lab. Pasteur went further and somehow used tweezers and a microscope (I do not conceive to understand how) to separate the tartaric acid crystals which he produced in the laboratory into piles of left and right handed molecules. He found that polarized light was rotated by the left handed molecules that he had selected in the same way the polarized light was rotated by the organic tartaric acid. He concluded that chiral molecules are responsible for the rotation of polarized light.So chiral molecules rotate light, but actually so does an individual achiral molecule! In an ensemble of achiral molecules each individual molecule may rotate the plane of the polarization, but the net rotation averaged over the ensemble will result in zero rotation. A mixture of two enantiomers in a 1:1 ratio (which is what you get when you create chemicals in the lab) is optically inactive because the rotation results in a zero net polarization rotation. When a reagent or catalyst is optically active the chiral product will also be optically active, or in the presence of chiral forces such as circularly polarized light this may also induce optical activity via enantimoeric excess in the products as well. Generally you can get optically active compounds in two ways 1) The reagent in already optically active. 2) The reaction of achiral but optically inactive precursors in a chiral optically active environment occurs. It takes an optically active molecule or chiral force to produce a product that is optically active.Most chemical reactions are not enantiomerically selective so that the initial reason for a completely homochiral biology on Earth remains a mystery just as when Biot and Pasteur discovered chirality through optical activity. Of course chirality is simply geometric in nature and thus this geometric asymmetry is what makes life chiral. Any molecule that contains a tetrahedral carbon or other central atom bonded to four different atoms or constituents will exist in enantiomeric forms; given that all biological molecules are at least this complicated, then (almost?) all biological molecules exist in enantiomeric forms. It may be that the chirality of biomolcules is simply a consequence of the emergent complexity of basic physics. The conditions necessary for a solution initially containing near equal number of chiral forms to evolve towards pure chirality has been explored (see Frederick Frank 1953) and is plausible. A tiny initial imbalance has spiraled out of control and now each successive generation of biomolecules on Earth is produced by the previous generation of chiral reagents, thus this is the why life is chiral. None of this explains how life is chiral, but a common answer is that because life can be chiral it is chiral.From this persepctive this topic is not so interesting, honestly. I have come to the conclusion that chriality is as it must be given that each generation of life is spawned from the previous generation under conditions which do have enantiomeric selection forces present. The question is why was left handed chirality chosen for life on our Earth?Now actually, the chirality of biomolecules is not just ... Read more »
Robert N. Compton, Richard M. Pagni, & Volume 48, 2002, Pages 219-261. (2002) The chirality of biomolecules. Advances In Atomic, Molecular, and Optical Physics, 219-261. info:/
I am continuously impressed by the publications that have appeared since Prof. Keith Fagnou's shocking passing a little over a year ago. The chemical community still mourns; it is clear from these post-mortem publications that Fagnou's - and his clearly dedicated and talented graduate students and post-docs - brilliance lives on. The chemistry that Fagnou has truly spearheaded, direct C-H functionalization, is a method of forming C-C, C-N, C-B, etc bonds without having to prepare one of the coupling partners, as in traditional transition-metal catalyzed cross-coupling reactions. Palladium, rhodium and ruthenium are commonly used catalysts in direct C-H functionalization reactions. Fagnou has published a great deal on arylation reactions of a wide variety of substrates and even a bit on direct benzylation reactions. Some fairly recent reviews are linked in a previous post.A recent publication in Journal of Organic Chemistry (doi: 10.1021/jo102081a), "Predictable and Site-Selective Functionalization of Poly(hetero)arene Compounds by Palladium Catalysis," published by David Lapointe and coworkers, explores the development of two approaches to selectively functionalizing multi-ring systems - 1) using site-selective reaction conditions, and 2) a pathway with a particular order of reactivity according to a concerted metalation-deprotonation (CMD) mechanism. It is well-known in the field that a great many (hetero)arenes can be functionalized with (painfully) rigorous fine-tuning of the catalyst, ligand, additives, and other reaction conditions. Some substrates have been more difficult to functionalize than others, and selectivity of particular positions on these rings is always an issue - this publication tackles both issues.To explore site-selective functionalization, the group used compounds with more than one available C-H bond for direct functionalization, and using multiple protocols specific for specific C-H bonds (Larossa's conditions for C2 arylation of indoles, Gaunt's Cu-catalyzed C3 arylation of indoles which is actually selective for meta to amido groups, and their own protocols for arylation of perfluorobenzenes and aromatic N-oxides) were able to successfully and selectively functionalize targeted C-H bonds in moderate yields. Here is an example with some decent yields, with reaction times ranging from 16 - 24 hours: The alternative approach relies upon the CMD pathway as the operative mechanism, which favors electron-deficient substrates. Several years ago, Echavarren published support of this mechanism by finding a preference for the most acidic C-H bond and requirement for a carbonate base, and Fagnou established the use of a pivalate additive, which was speculated to play a crucial role via CMD. A recent mechanistic paper with aromatic N-oxides as the substrates strongly supports this mechanism. The metal first inserts into the aryl-X bond, as expected, and in the key transition state, the pivalate coordinated to the metal deprotonates the C-H bond while the palladium forms a bond to the same C. Reductive elimination (not shown) releases the arylated product.In the current paper DFT calculations were found to agree quite well compared to competition reaction results of a series of heterocycles to elucidate the order of reactivity of the substrates. Those presented in the paper are as follows, in order of reactivity - this is extremely convenient for the synthetic chemist who would like to utilize this chemistry. And it's just plain neat - the kind of thing that will hopefully end up in a textbook someday. (Note: the last two substrates are either switched in the text or switched in the image - they don't agree in the paper and I haven't looked at the supporting information closely.)Reaction conditions: 0.5 eq. of each of two heteroarenes in the competition experiment, 0.125 eq. 4-bromotrifluorobenzene, Pd(OAc)2 5 mol%, PCy3.HBF4 (10 mol%), PivOH (30 mol%), K2CO3 (1.5 eq.), DMA (0.3M), 100ºC. And finally, for an example of the method in action - note that the difference between using this method and the previously described is that here, there aren't necessarily general optimized conditions available for each of the substrate classes here. Examples of a few of these are peppered throughout the arylation literature but they aren't like indoles, pyridines, N-oxides, perfluorobenzenes, imidazoles, and pyrazoles and don't have their own special set of conditions (that I'm aware of at the moment). Yields of included substrates range from 65-80%. Instead of optimizing conditions for each, the site of reactivity can be predicted with good specificity - here the indolizine C-H bond over the more electron-rich thiophene's:Instead of an aryl bromide, benzyl chloride can be used as the coupling partner as well, with published yields from 55-84%. ... Read more »
Lapointe, D., Markiewicz, T., Whipp, C. J., Toderian, A., & Fagnou, K. (2011) Predictable and Site-Selective Functionalization of Poly(hetero)arene Compounds by Palladium Catalysis. Journal of Organic Chemistry. info:/10.1021/jo102081a
Did you know that salmon rely on their sense of smell (olfaction) for nearly every aspect of their lives, from locating food to avoiding predators? ... Read more »
Arthur Hasler, & Warren Wisby. (1951) Discrimination of Stream Odors by Fishes and Its Relation to Parent Stream Behavior. The American Naturalist, 85(823), 223. DOI: 10.1086/281672
W.J. Wisby, & A.D. Hasler. (1954) Effect of olfactory occlusion on migrating silver salmon (O. kisutch). Journal of the Fisheries Research Board of Canada, 472-478. info:/
Yamamoto, Y., Hino, H., & Ueda, H. (2010) Olfactory Imprinting of Amino Acids in Lacustrine Sockeye Salmon. PLoS ONE, 5(1). DOI: 10.1371/journal.pone.0008633
Tierney, K., Sampson, J., Ross, P., Sekela, M., & Kennedy, C. (2008) Salmon Olfaction is Impaired by an Environmentally Realistic Pesticide Mixture. Environmental Science , 42(13), 4996-5001. DOI: 10.1021/es800240u
Sandahl, J., Baldwin, D., Jenkins, J., & Scholz, N. (2004) Odor-evoked field potentials as indicators of sublethal neurotoxicity in juvenile coho salmon (Oncorhynchus kisutch) exposed to copper, chlorpyrifos, or esfenvalerate. Canadian Journal of Fisheries and Aquatic Sciences, 61(3), 404-413. DOI: 10.1139/f04-011
In order to perform its function, protein should be properly folded. Therefore stability of this proteins’ native state is crucial for its function. Denatured protein can be toxic the cell and requires specialised machinery to degrade it, thus compromising cells fitness. Having a denatured protein is not equal to just not having a functional one, it is equal to not having a functional one and hiving some costly junk.Since stability is so crucial for proteins function, it must leave its trace in the patterns of amino acid conservation. Bioinformatic studies show that there is a strong correlation between the Surface Accessible Area (SAA) of the residue and its conservation, or, simply speaking, conserved residues are mostly buried inside the protein. That sounds logical – the core should be more important for protein stability than its outer shell. The outer residues, on the other hand, can be rearranged in order to change proteins binding selectivity after the duplication event, thus leading to divergence of the two copies. But lets get back to the core.Basic thermodynamics relationships link protein stability to parameters like Gibbs free energy (ΔG), enthalpy (ΔH), entropy (ΔS), heat capacity (C, or, to be specific heat capacity at constant pressure, Cp) and absolute temperature (T). And adaptation to extreme temperatures gives us a sticking example of thermodynamics shaping protein evolution. But first let us start with some basic theory - I know that sounds painful, but please stay with me for a moment!Gibbs free energy is divided into enthaplic and entropic components (ΔG = ΔH - TΔS). By the definition of Gibbs energy, in order for the protein to be stable, G of folding should be negative, and when it is positive, the protein unfolds. Both of components of ΔG are changing with temperature. Enthalpy is changing linearly, with the proportionality coefficient being heat capacity (ΔCp, ΔH(T) = ΔH(T0) + ΔCp(T-T0)). Heat capacity is the amount of heat needed to change the temperature of protein for one degree. Entropy also changes with temperature, though in a bit more complex way (ΔS = ΔS(T0) + ΔCpln(T/T0). When we combine the two, we get this:ΔG(T) = ΔG(T0) + ΔCp(T-T0) - ΔCpTln(T/T0)This is a very interesting relationship. It gives ΔG(T) its characteristic shape with a maximum corresponding to the T of maximums stability, and two denaturation temperatures (on the graph below I plot –ΔG, rather than ΔG just so that the plot looks nicer). We are all familiar with the protein denatureation at high temperatures (we all boiled eggs!), but at lower temperatures? Well, this one happens as well, but very, very slowly, as all the reactions tend to at low temperatures, so we do not notice it that much. However, indeed, some proteins are better off when stored at -20Co, than at -80Co. Heat capacity is intimately linked to the above-mentioned solvent accessible area (SAA). The reason for that is that it is water surrounding the protein what gives its heat capacity. Water molecules next to the protein are restricted in their freedom, they are essentially frozen, and ice, as we know, has tremendous heat capacity. When the protein denatures, its SAA increases, and so does the heat capacity. Heat capacity change upon denaturation in turn is determining the shape of folding ΔG dependence on temperature (see equation above). And now we are primed to discuss how the extermophylic proteins cope with the high temperatures. One can imagine two obvious solutions. First, they could increase their stability (ΔG) (curve a). However, this would result in a bit too stable proteins that will be very hard to degrade, and this is not good for metabolism. Also, they will be too rigid, and flexibility is necessary for protein function. Second, they could move their temperature of maximum stability (curve b). In reality they do something completely different! They decrease the ΔCp instead, flattening the G curve. So how do they decrease the ΔCp? Well this is all about the nature of the denatured state. Δp is proportional to ΔSAA of protein unfolding, but proportionality is different for hydrophobic residues (these freeze water well, thus proportionality coefficient is high) and hydrophilic ones (these are similar to water in their nature, and thus do not restrict its movement too much, and the proportionality coefficient is lower). Thermophilic proteins enrich normally hydrophobic protein core with polar residues, forming salt bridges and dipole-dipole pairs. This results in more rigid structure, thus you still pay in flexibility somewhat, therefore if there is no need for extreme temperatures, hydrophobic core is better. Modifying protein core is not an easy task since you need to compensate for one substitution with another (say, you have a positively charged residue, and now in order to compensate it you need a negatively charged one). Moving in the other direction (Thermophilic to mesophilic) would be equally tricky. Therefore keeping your temperature stable – just like we do! – allows avoiding all these complicated thermodynamic matters altogether.References: ... Read more »
Fu H, Grimsley G, Scholtz JM, & Pace CN. (2010) Increasing protein stability: importance of DeltaC(p) and the denatured state. Protein science : a publication of the Protein Society, 19(5), 1044-52. PMID: 20340133
Franzosa EA, & Xia Y. (2009) Structural determinants of protein evolution are context-sensitive at the residue level. Molecular biology and evolution, 26(10), 2387-95. PMID: 19597162
Drummond DA, & Wilke CO. (2008) Mistranslation-induced protein misfolding as a dominant constraint on coding-sequence evolution. Cell, 134(2), 341-52. PMID: 18662548
Geiler-Samerotte KA, Dion MF, Budnik BA, Wang SM, Hartl DL, & Drummond DA. (2011) Misfolded proteins impose a dosage-dependent fitness cost and trigger a cytosolic unfolded protein response in yeast. Proceedings of the National Academy of Sciences of the United States of America, 108(2), 680-5. PMID: 21187411
Loladze VV, Ermolenko DN, & Makhatadze GI. (2001) Heat capacity changes upon burial of polar and nonpolar groups in proteins. Protein science : a publication of the Protein Society, 10(7), 1343-52. PMID: 11420436
DePristo MA, Weinreich DM, & Hartl DL. (2005) Missense meanderings in sequence space: a biophysical view of protein evolution. Nature reviews. Genetics, 6(9), 678-87. PMID: 16074985
A very common chemical conversion (important to pharmaceutical and other syntheses), which in its most gentle application generates much waste, has now been rendered far more environmentally friendly.... Read more »
Dai, C., Narayanam, J. M. R., & Stephenson, C. R. J. (2011) Visible-light-mediated conversion of alcohols to halides. Nature Chemistry. DOI: 10.1038/NCHEM.949
Pharmaceutical companies sometimes get a bad rap, but most people don’t realize just how labor/money-intensive the process of drug discovery is. A recent paper offers a little glimpse at the process – although this research was done by chemists at … Continue reading →... Read more »
MacMillan, K., Naidoo, J., Liang, J., Melito, L., Williams, N., Morlock, L., Huntington, P., Estill, S., Longgood, J., Becker, G.... (2011) Development of Proneurogenic, Neuroprotective Small Molecules. Journal of the American Chemical Society. DOI: 10.1021/ja108211m
Bacteria which possess genetic damage that normally prevents reproduction in a nutrient-deficient medium can be saved by expression of artificial proteins, an important step towards constructing artificial life.... Read more »
Fisher, M. A., McKinley, K. L., Bradley, L. H., Viola, S. R., & Hecht, M. H. (2011) De Novo Designed Proteins from a Library of Artificial Sequences Function in Escherichia Coli and Enable Cell Growth. PLoS ONE, 6(1). DOI: 10.1371/journal.pone.0015364
Happy new year! I hope 2011 brings us everything 2010 promised but failed to deliver. Namely jetpacks and first contact. But in the meantime we will have to enjoy these other exciting discoveries! Self-repairing solar cells. One of the advantages that plants have over man-made solar cells is that whenever one of the dye molecules [...]... Read more »
Nanotechnology researchers working on self-powered nanodevices - nanoscale systems that scavenge energy from their surrounding environment - have been experimenting with various power sources ranging from piezoelectric systems to sound. However, the most abundant energy available in biosystems is chemical and biochemical energy, such as glucose. Researchers in China have now reported an nanowire-based biofuel cell based on a single proton conductive polymer nanowire for converting chemical energy from biofluids into electricity, using glucose oxidase and laccase as catalyst. The output of this biofuel cell is sufficient to drive pH, glucose or photon sensors. The high output power, low cost and easy fabrication process, large-scale manufacturability, high 'on-chip' integrability and stability demonstrates its great potential for in vivo biosensing.... Read more »
Pan, C., Wu, H., Wang, C., Wang, B., Zhang, L., Cheng, Z., Hu, P., Pan, W., Zhou, Z., Yang, X.... (2008) Nanowire-Based High-Performance “Micro Fuel Cells”: One Nanowire, One Fuel Cell. Advanced Materials, 20(9), 1644-1648. DOI: 10.1002/adma.200700515
The past year has been a great year for science with major advances in several areas. Too many exciting results to mention here. Instead, to reflect about the past year I have chosen a representative paper for each month of the year that I hope can serve as an example of the great science going [...]... Read more »
Chuang, T., Allan, M., Lee, J., Xie, Y., Ni, N., Bud'ko, S., Boebinger, G., Canfield, P., & Davis, J. (2010) Nematic Electronic Structure in the "Parent" State of the Iron-Based Superconductor Ca(Fe1-xCox)2As2. Science, 327(5962), 181-184. DOI: 10.1126/science.1181083
Lin, Y., Dimitrakopoulos, C., Jenkins, K., Farmer, D., Chiu, H., Grill, A., & Avouris, P. (2010) 100-GHz Transistors from Wafer-Scale Epitaxial Graphene. Science, 327(5966), 662-662. DOI: 10.1126/science.1184289
Kelzenberg, M., Boettcher, S., Petykiewicz, J., Turner-Evans, D., Putnam, M., Warren, E., Spurgeon, J., Briggs, R., Lewis, N., & Atwater, H. (2010) Enhanced absorption and carrier collection in Si wire arrays for photovoltaic applications. Nature Materials. DOI: 10.1038/nmat2635
Ergin, T., Stenger, N., Brenner, P., Pendry, J., & Wegener, M. (2010) Three-Dimensional Invisibility Cloak at Optical Wavelengths. Science, 328(5976), 337-339. DOI: 10.1126/science.1186351
Liang, Y., Xu, Z., Xia, J., Tsai, S., Wu, Y., Li, G., Ray, C., & Yu, L. (2010) For the Bright Future-Bulk Heterojunction Polymer Solar Cells with Power Conversion Efficiency of 7.4%. Advanced Materials, 22(20). DOI: 10.1002/adma.200903528
Yu, X., Onose, Y., Kanazawa, N., Park, J., Han, J., Matsui, Y., Nagaosa, N., & Tokura, Y. (2010) Real-space observation of a two-dimensional skyrmion crystal. Nature, 465(7300), 901-904. DOI: 10.1038/nature09124
Chadov, S., Qi, X., Kübler, J., Fecher, G., Felser, C., & Zhang, S. (2010) Tunable multifunctional topological insulators in ternary Heusler compounds. Nature Materials, 9(7), 541-545. DOI: 10.1038/nmat2770
Lin, H., Wray, L., Xia, Y., Xu, S., Jia, S., Cava, R., Bansil, A., & Hasan, M. (2010) Half-Heusler ternary compounds as new multifunctional experimental platforms for topological quantum phenomena. Nature Materials, 9(7), 546-549. DOI: 10.1038/nmat2771
Bae, S., Kim, H., Lee, Y., Xu, X., Park, J., Zheng, Y., Balakrishnan, J., Lei, T., Ri Kim, H., Song, Y.... (2010) Roll-to-roll production of 30-inch graphene films for transparent electrodes. Nature Nanotechnology, 5(8), 574-578. DOI: 10.1038/NNANO.2010.132
KLEMENT, W., WILLENS, R., & DUWEZ, P. (1960) Non-crystalline Structure in Solidified Gold–Silicon Alloys. Nature, 187(4740), 869-870. DOI: 10.1038/187869b0
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Toyabe, S., Sagawa, T., Ueda, M., Muneyuki, E., & Sano, M. (2010) Experimental demonstration of information-to-energy conversion and validation of the generalized Jarzynski equality. Nature Physics, 6(12), 988-992. DOI: 10.1038/nphys1821
I have been unable to blog for the past few days because I was busy moving to Chapel Hill for a postdoc at UNC Chapel Hill. I am very excited about this move and my upcoming research which is going to involve protein design and folding. Regular blogging will resume soon. Until then, happy holidays, and I will leave you with the following interesting paper published by a group from my new institution.One of the abiding puzzles in the origin of life is to explain how life arose in the relatively small amount of time it had to evolve on the planet. From a chemical perspective, this entails explaining how especially slow chemical reactions could have contributed to the complexity of life. In a new paper in PNAS, a group from UNC suggests part of a possible solution to the puzzle by demonstrating that slow reactions especially are accelerated by temperature much more than fast reactions. Recall from college physical chemistry that the rate of a typical reaction roughly doubles with ten degree rise in temperature. As the authors note, this bit of textbook wisdom is off the mark when it comes to many important reactions and needs to be appended.They look at certain important reactions like the hydrolysis of phosphate monoesters and find that these reactions are accelerated not two or a few fold but many million fold with a rise in temperature. The increase in rate would have been significant especially under the hot, primordial conditions present on earth during its early days. Now this acceleration is free-energetic and basically corresponds to a favorable change in either the entropy or the enthaply of activation. The authors measure both this variables and find that the crucial change is in the enthalpy. It's interesting to note that a favorable change in the enthalpy would entail forming stronger interactions including hydrogen bonds between substrate and enzyme, and this is exactly the kind of process you would imagine happening during the optimization of biomolecular interactions during evolution. In fact, recent research suggests that this process of optimizing enthalpy is also mirrored during drug discovery. The authors end by explaining why a catalyst that impacted enthalpy rather than entropy favorably would have had a selective advantage in rate acceleration as the environment later cooled (and entropy became unfavorable).Amusingly, the paper has come under criticism from some unexpected quarters, from none other than folks from the infamous 'Discovery' Institute which is funded and run by creationists. In the view of these esteemed 'scientists', the paper provides no evidence that the slow reactions which were accelerated were in fact ones which were important during the origin of life. The DI crowd seems to have fundamentally misjudged the nature of origins of life research; it's more speculative than many other fields but still remains scientific. More importantly, the criticism seems to have completely missed the fact that the general hypotheses proposed by the authors- that all slow reactions could have been vastly accelerated by temperature on a hot primordial planet- is independent of the exact nature of these reactions which may or may not have contributed to life's origins. As usual, miss the forest for the trees.Stockbridge, R., Lewis, C., Yuan, Y., & Wolfenden, R. (2010). Impact of temperature on the time required for the establishment of primordial biochemistry, and for the evolution of enzymes Proceedings of the National Academy of Sciences, 107 (51), 22102-22105 DOI: 10.1073/pnas.1013647107... Read more »
Stockbridge, R., Lewis, C., Yuan, Y., & Wolfenden, R. (2010) Impact of temperature on the time required for the establishment of primordial biochemistry, and for the evolution of enzymes. Proceedings of the National Academy of Sciences, 107(51), 22102-22105. DOI: 10.1073/pnas.1013647107
As Tom Lehrer once sang on his winterval carol: “Christmas time is here, by golly, Disapproval would be folly, Deck the halls with hunks of holly, Fill the cup and don’t say ‘when.’ Kill the turkeys, ducks and chickens, Mix the punch, drag out the Dickens, Even though the prospect sickens, Brother, here we go [...]... Read more »
Mark Miodownik. (2005) Facts not opinions? Devoloping both the physical and aesthetic properties of materials. Nature Materials, 4(7), 506-508. DOI: 10.1038/nmat1416
It’s the holiday season, which means it’s time to start thinking about the flu! The flu is notoriously tricky to prevent with vaccines, partly because there are so many strains of influenza virus, and each strain is constantly undergoing genetic … Continue reading →... Read more »
Bryan B. Hsu, Sze Yinn Wong, Paula T. Hammond, Jianzhu Chen, and Alexander M. Klibanov. (2010) Mechanism of inactivation of influenza viruses by immobilized hydrophobic polycations. Proceedings of the National Academy of Sciences. info:/10.1073/pnas.1017012108
Stopping at the charity field on the way back from pollinating, I noticed a ripening rye cover crop the next field over - and decided to look for my friend, ergot.*
I couldn't believe my luck! There were little black pods sprouting from rye spikes all over the edge of the field. This is a very exciting creature to a plant pathologist - and one that's had quite an impact on European history...
Ergot is a plant disease caused by Claviceps purpurea, a member of one of my favorite fungal families, the Clavicipitaceae. Its lifecycle begins in the spring when infective spores are forcibly ejected from reproductive structures that sprout from overwintering pods of black, hardened mycelium called "sclerotia." These spores are launched into the air in the same season that rye and other susceptible grasses are flowering and float on the breeze until they come in contact with one of these plants. Upon landing on a susceptible flower's stigma, the spore germinates and grows into the ovary, destroying it and growing into a fluffy mass of hyphae - covered with asexual spores and a nectar-like substance that encourages insects to track it to yet to be infected flowers elsewhere.
While spores continue to infect new rye flowers, our original fungal infection continues to develop - growing into a long, thin and progressively harder pod where a particular rye grain should have been. One or many of these sclerotia (aka "ergots") may be found in any given rye head, where their little black nubs can be seen poking out of the head (the one in the picture is unusually large). Many of these sclerotia fall from their host during harvesting. They survive the winter in the litter of the field, protected in part by a potent mix of more than 40 toxic and psychotropic alkaloids within them, including lysergic acid diethylamide (LSD) derivatives.**
While we're well aware of the danger inherent in these little black pods today (and can remove them from infested grain), Medieval Europeans were not so fortunate. Ergots were routinely milled into flour, and in bad years could reach frighteningly high levels. The ergots were not identified as a source of this disease until 1670 (partially because these little sclerotia were so common that they were included in botanical illustrations of rye!). The primary effects of ergot alkaloid poisoning include hallucination and vasoconstriction. The resulting loss of blood flow to the extremities of afflicted persons produced intense burning sensations, followed by blackening and the loss of hands and feet - a condition commonly known as St. Anthony's Fire (so named due to the symptoms and the religious order that became known for caring for the afflicted).*** This disease was especially tragic as it was most likely to strike the poorest individuals and intensified the worst harvests - rye is extremely cold tolerant and was, for many Europeans, either a staple or food of last resort.
Historians have invoked outbreaks of this disease (legitimately or not) to help explain all manner of sociological unrest, including the European and Salem witch trials, the "Great Awakening" and the French Revolution. Peter the Great's crusade for a warm water port at Constantinople was ended when an ergotism outbreak poisoned his soldiers and horses. In recent centuries, doctors have taken advantage of these chemical cocktails to induce labor, prevent postpartum hemorrhage and treat migraines. Some domesticated strains have been developed that contain 20% alkaloid chemicals by sclerotium dry weight (versus the natural 1%).
Today, ergotism is thankfully known primarily as a disease of livestock (though outbreaks occasionally occur where starving people are forced to eat contaminated grain or wild grasses). In the present, as in the past, unlucky livestock can be diagnosed by the loss of tails, ear tips and eventually feet.
Can't get enough of the Clavicipitaceae?
A sister of Claviceps is Cordyceps, the parasitic "caterpillar fungus" that sprouts from infected insects and is being driven to oblivion by harvesters. One of a handful of fungi able to colonize living insects (and then fruit from within them), Cordyceps sinensis is prized for its mythical curative powers and the "loosing of miraculous athletic feats!"
Recently, many new Cordyceps species have been discovered in tropical regions where they are capable of zombie-fying certain ants - forcing them to climb to exposed perches where they die and sprout infective spores.
David Attenborough narrates this incredible 3 minute video (and time-lapse photography!) of insects enslaved and succumbing to Cordyceps.
The Clavicipitaceae also contains a number of grass endophytes (Epichloe, Balansia, Atkinsonella and Myriogenospora). These symbiotic fungi live between and around the shoot and leaf cells of certain grasses and sedges. Some of these fungi can penetrate their host's seeds (a rare feat for a microbe!), allowing them to spread to the next generation. Others inhibit flowering of their hosts (decreasing sexual recombination that might allow the host to repel future generations of fungi). One species does this by binding the tips of leaves and flowers, preventing proper development and causing the grass leaves to stick in big loops. Another, which infects a grass species with both closed (inbreeding) and open (outcrossing) flowers, spares the inbreeding flowers and destroys the outcrossing flowers. Meanwhile, these fungi produce sugary masses of sexual spores that are cross-pollinated by insects.
So do the manhandled grasses get anything out of this? Yep! Like their other family members, these fungi are packed full of alkaloids, which in this case can confer drought and herbivore resistance to the host. It's actually a real problem in forage, where it causes diseases such as fescue toxicosis (warning: this review contains some gross pictures of symptoms such as "fescue foot"). This disease is a major livestock disease of the eastern U.S. and shares some of the symptoms of ergot poisoning, slowing weight gain at best and killing livestock at worst (another more colorful name for this type of endophyte poisoning is "the blind staggers"). In the case of fescue toxicosis, prevention (there is no cure) is accomplished by managing pastures for the absence of endophytes (or the presence of low-toxin strains).
* It was July, and and the winter squash and melons were coming on strong. The beans were already gone and the cantaloupes (for non-Americans, muskmelons) were so incredibly ripe that they might as well have been filled with an 80+ degree sorbet. I opened one up with my corn knife and shared it with my co-workers. Not a good day to have a beard, but a great end to a long day in the corn fields.
** I once knew a girl from Oberlin who claimed that generations of students cultivated this hallucinogenic fungus on rye bread in a closet. She also claimed that there was a girl who kept a pet bat under her shirt at all times...
*** Not to be confused with St. Elmo's fire.
Alexopoulos, C.J., Mims, C.W., Blackwell, M. 1996. Introductory Mycology. John Wiley & Sons.
... Read more »
Stone, R. (2008) MYCOLOGY: Last Stand for the Body Snatcher of the Himalayas?. Science, 322(5905), 1182-1182. DOI: 10.1126/science.322.5905.1182
OK, the second paper I ran into today is a perfect match for the paper by Khanna and Ranganathan I just dicussed in the Commercial or Proprietary? post. So perfect, in fact, that it I should have really combined them. But since the other post is already infecting the WWW, I'll have to post this update.
Yap wrote up a paper on PaDEL-descriptor: An open source software to calculate molecular descriptors and fingerprints (doi:10.1002/jcc.21707), and Table 2 is quite like Table 1 in the paper by Khanna and Ranganathan. Not only does Yap correctly differentiates between product cost and license, it also details the descriptor type count and descriptor value count. It is a good exercise to compare those two tables yourself.
Yap, C. (2010). PaDEL-descriptor: An open source software to calculate molecular descriptors and fingerprints Journal of Computational Chemistry DOI: 10.1002/jcc.21707... Read more »
Yap, C. (2010) PaDEL-descriptor: An open source software to calculate molecular descriptors and fingerprints. Journal of Computational Chemistry. DOI: 10.1002/jcc.21707
An artificial wetland in central Florida greatly improved municipal and industrial wastewater quality for at least 18 months.... Read more »
Lazareva, O., & Pichler, T. (2010) Long-term performance of a constructed wetland/filter basin system treating wastewater, Central Florida. Chemical Geology, 269(1-2), 137-152. DOI: 10.1016/j.chemgeo.2009.06.006
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