"Duh" newspiece of the day

Stay thin to cut cancer, study says

Unclear? No, it's nuclear

Nuclear energy promises to be the safest, most efficient and reliable source of energy in the fight against carbon-emissions and climate change. Yet there is deep-rooted opposition to it in the minds of the public and policy makers, mainly based on a dissonance between beliefs and reality. It is important for the public to transcend gut reactions, political pandering and partisanship and have balanced and sound knowledge of this very important energy source...

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The only existing O-H...F-C bond...not

This is a beautiful piece of data re-interpretation. A few years ago, there was a report published about a compound which supposedly demonstrated the only instance of a solution O-H...F-C hydrogen bond. This seemed to provide some support for hydrogen bonding involving fluorine.

Now a Spanish group has published a nice paper in CC that provides a refutation and re-interpretation of the data that along with some calculations, indicates that the observed data is not due to a C-F...H-O hydrogen bond, but simply due to steric hindrance that makes the three fluorines of a CF3 group non-equivalent. In the former interpretation, it was assumed that the non-equivalence of two Fs of this group with the third F indicated that the third F was involved in hydrogen bonding. The new interpretation says that it is steric hindrance that prevents rapid rotation of the CF3 group, and makes the three Fs non-equivalent. Calculations support the interpretation.

Thus, now we will have to look for other instances in which there is bonafide C-F...H-O bonding. Quite a neat piece of careful data analysis supported by crystallography and quantum chemical caclulations.

Another fact mentioned in the paper reminds me of one of the more memorable papers that I have read; Stanford's Eric Kool's demonstration that difluorotoluene- an isostere of thymine in which Ns are replaced by Cs and Os are replaced by Fs- behaves like thymine when DNA polymerase inserts it opposite adenine.

Reference:
Is there any bona fide example of O–HF–C bond in solution? The cases of HOC(CF3)2(4-X-2,6-C6H2(CF3)2) (X = Si(i-Pr)3, CF3)
Chem. Commun., 2007, 4384 - 4386, DOI: 10.1039/b710304b

Please don't kill the message

It is very important not to let James Watson's statements stifle or intimidate scientists who are engaged in investigating all kinds of differences between various races. They need our protection and support now more than ever...

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Who is the fairer one; H or X?

There's a fair amount of discussion going on at Kinasepro and TotMed regarding halogen bonding, a pretty interesting topic. I have read a few reports about it, but questions still linger. One of the questions raised by a commenter at KP was "How can a X-bond (halogen bond) be as strong as a H-bond?".

With good timing, there is a paper just published in JACS that seeks to investigate that kind of issue. It deals with competition between X and H bonding. The authors considered the four relatively simple molecules shown above that are studded with strong H-bond acceptors (pyridinyl and imidazolyl N), weak H-bond donor (imine C-H) and weak and halogens as X-bond acceptors and donors. Three of the molecules were the same except for different halogens.

The authors obtained several crystal structures, of the molecules themselves, as well as their complexes with the other molecules. The results indicate that a strong-strong H-bond donor-acceptor interaction (imadazole/pyridine N...OH hydrogen) trumps any X-bonding interaction, which is probably not too surprising. Weak X...X and N...X interactions such as Br...Br and N...Br are also trumped by weak-strong H-bonding interaction (imine C-H...pyridine N). However, N...I interactions do seem to be able to trump imine C-H...pyridine N interactions, although not strong-strong H-bonds.

Does this prove the general case of most X...X or X...N bonds being weaker than H-bonds? Yes, but not in the context of a crystal really, because crystallization is a hideously complex phenomenon to predict since it involves many subtle interactions and the sum of their costs and benefits. In a crystal or a protein for that matter, a H-bond could very well be sacrificed for a X-bond, not because the X-bond is per se stronger than the H-bond, but because the other parts of the molecule could interact in a way that is more favourable in the orientation with the X-bond rather than the H-bond.

It would also have been nice if they had mixed together the different halogen containing molecules. And I am still waiting for a good theoretical chemist to explain how the interaction can be worth 4-5 kcal/mol.

Reference:
Structural Competition between Hydrogen Bonds and Halogen Bonds
Christer B. Aakeröy,* Meg Fasulo, Nate Schultheiss, John Desper, and Curtis Moore
J. Am. Chem. Soc., ASAP Article 10.1021/ja073201c

Don't squelch eccentricity

Distinguished scientists including Edward O. Wilson (who for the record despised Watson before) and Richard Dawkins are now coming to James Watson's support. I suspect that the gut reaction that surfaced right after he made his statements obscured any kind of objective reasoning and patient analysis, as often happens with such socially explosive issues. Nobody can say that he had every justification for saying what he did, but more are now rallying to his side and denouncing his dismissal from Cold Spring Harbor and the cancellation of his lecture at the Science Museum. I have already stated my opinion in the last post; while the lecture cancellation was probably more aimed by the Science Museum at avoiding bad press, his dismissal from Cold Spring was unwarranted. One interesting point of view says that he in fact should have been allowed to appear at the Museum and quizzed in detail about his statements.
Robin McKie in the Guardian reports:

"In the end, Watson decided to return home, so no meetings occurred, a move that has dismayed many scientists who believed that it was vital Watson confront his critics and his public. 'What is ethically wrong is the hounding, by what can only be described as an illiberal and intolerant "thought police", of one of the most distinguished scientists of our time, out of the Science Museum, and maybe out of the laboratory that he has devoted much of his life to, building up a world-class reputation,' said Richard Dawkins, who been due to conduct a public interview with Watson this week in Oxford.

Nor is it at all clear that Watson is a racist, a point stressed last week by the Pulitzer-winning biologist E O Wilson, of Harvard University. In his autobiography, Naturalist, Wilson originally described Watson, fresh from his Nobel success, arriving at Harvard's biology department and 'radiating contempt' for the rest of the staff. He was 'the most unpleasant human being I had ever met,' Wilson recalled. 'Having risen to fame at an early age, [he] became the Caligula of biology. He was given licence to say anything that came into his mind and expected to be taken seriously. And unfortunately he did so, with casual and brutal offhandedness.'

That is a fairly grim description, to say the least. However, there is a twist. There has been a rapprochement. 'We have become firm friends,' Wilson told The Observer last week. 'Today we are the two grand old men of biology in America and get on really well. I certainly don't see him as a Caligula figure any more. I have come to see him as a very intelligent, straight, honest individual. Of course, he would never get a job as a diplomat in the State Department. He is just too outspoken. But one thing I am absolutely sure of is that he is not a racist. I am shocked at what has happened to him.'

I especially find Wilson's remarks revealing, because Wilson has always been known to be a compassionate, fair and objective scientist who would be loathe to offer unabashed support for pet ideas and people. I have read several of his books and never have found him to be biased or narrow-minded. I think that him saying something like this about Watson, a man who was his bete noire for years, surely says something. And Wilson's depiction of himself and Watson as the two grand old men of American biology is quite accurate. The two grand men made a rare appearance on Charlie Rose quite recently.

"Don't silence the scientists"

Susan Blackmore's quips on Watson and academic freedom. Particularly sensible is this:

Surely a society based on denying a possible truth is not a healthy one. If there are such differences we need to be absolutely clear that they do not mean that some groups are intrinsically inferior, superior, or more or less deserving. If it is true that children of different races, by and large and on average, differ in their abilities, then we need an education system that encourages and develops all those varied abilities rather than one narrowly and rigidly based on glorifying the particular kind of intelligence and academic achievement that comes more easily to the dominant group."

I am not so sure that cancelling his lecture at the Science Museum was uncalled for; I see it more as an angry rap on the old man's hand. On the other hand, I now am agreeing that suspending him from his CSHL job does not serve much of a purpose, and reflects badly on respecting academic freedom. After all, institutions have been known to distance themselves from their employees, especially academic ones, and most people don't equate institutions' opinions with those of their employees. For example, should MIT fire Noam Chomsky because he has sometimes espoused what some have claimed as radical and bigoted views? Of course not, and here the issue clearly is about academic freedom. If Lehigh University can simply get away with putting a disclaimer on their site distancing themselves from Michael Behe (whose creationist leanings are much more crackpot than even Watson's, if not as offensive-sounding), then why can't CSHL?

Kornberg goes nano

Roger Kornberg is a remarkably versatile man. After the discovery of the structure of the gigantic transcription RNA polymerase complex that bagged him a Nobel Prize last year (and brought in shouts of "No chemistry Nobel to a biologist!"), he has now unravelled the structure of a gold-thiolate cluster at the exquisite resolution of 1.1 A, clearly a more "pure" chemistry achievement. The paper made the front page of this week's Science and has been called a tour de force.

For anyone liking crystals this will be delicious. The pictures in the SuppInfo are even better. The structure may lead to a revision of other previously thought structural notions.

Commentary
Paper DOI: 10.1126/science.1148624

When scientists get old and boring...

James Watson has turned from provocative and scientific to racist-sounding and irrational. A pity...

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Paradise regained?

It should be a resounding slap in the face of global warming contrarians, now that Al Gore and the IPCC have won the Nobel Peace Prize:

"for their efforts to build up and disseminate greater knowledge about man-made climate change, and to lay the foundations for the measures that are needed to counteract such change".

Now of course, that does not mean all our problems are solved, and that policy will now proceed smoothly. Fox News and others will still find good excuses to discredit the prize. They will probably even say that the prize makes Al Gore an even richer man while the rest of the world grows poorer. They will also speculate about the gratuitous lobbying that went on in their opinion in the deliberations. In addition, falling back on Gore's personal lifestyles is an argument which they could never let go of. Whatever.

The prize was expected and it's probably not very surprising even if a happy circumstance. There are still miles to go before we bring carbon emissions under control though, and even if we stop today, many deleterious effects will continue to be observed, and curbing those effects is going to be a complex scientific and political process. In fact, the prize also does not mean that climate change is now suddenly fully understood. But this is at least a partial vindication.

What I feel happiest about is not just that the Prize was awarded to Gore and the IPCC, but that it was also awarded to those thousands of scientists, who starting in the 1950s travelled to the farthest reaches of the planet to drill ice cores, document effects on sea level, snow cover, wildlife habitats and human populations. It's also a big thank you to those like James Hansen who have tirelessly worked in the face of political suppression to build computer models and relentlessly weed out the uncertainties (especially those caused by forcings). In fact, in my opinion Hansen himself deserved this prize, but it may been unfair to some other scientists.

Awarding one half to the IPCC for "building up" the scientific background of climate change and the other half to Gore for "disseminating" this knowledge seems like an apt split. The IPCC has constantly published reports since 1989 on climate change. It's latest report in 2007 was an encapsulation of cutting edge research and the most current conclusions it has drawn, which have not changed substantially from the 2001 report. The main contribution the IPCC has made between the two reports is to weed out uncertainties caused by "forcings"- factors including artificial ones like fossil fuel emissions and aerosols and natural ones like volcanic emissions that can either increase or decrease global temperatures. The problem previously was that some of these factors, especially those decreasing temperatures, had large uncertainties and so their potential balancing impact on CO2-induced warming could not be evaluated well. However, much progress was made between 2001 and 2006, and in its latest report the IPCC concluded that the "negative" forcings were much less than what was needed to counter the "positive" forcings. I would strongly suggest reading the IPCC summary. Anyone who reads it and still strongly suspects global warming needs to have immediate access to a dictionary and the mental asylum.

This is the first Nobel Prize for climate change as such, but it should be noted that one was given earlier for Chemistry to scientists who discovered the destruction of the ozone layer by CFCs. That research was a resplendent example of how science can starkly reveal the effects of human activities on the environment and force everyone to reconsider their way of life.

On the political front, George Bush and his yes-men can now do nothing more than concede to the grim reality of climate change, although it will be hardly surprising if they still don't. A couple of months ago, Bush stood in the White House Rose Garden and endorsed the 2007 IPCC report and human contributions to climate change. As Chris Mooney points out, he could have done exactly the same thing in 2001, when much of the science was equally well-known. But politicians and especially the current administration thrive on uncertainties in a perverted manner; while scientists thrive on uncertainties because they will improve understanding, politicians thrive on the same uncertainties so that they can cherry pick and try to discredit the entire enterprise.

The beauty of science however is that it always continues to progress, through mistakes as well as triumphs, and this is a fact which thwarts even the most powerful politicians' motives. Even if men in power can score temporary political points by discrediting science, they forget that science has simply retreated beyond the stage, where it continues to march on through the tedious work of dedicated scientists. This exact same principle applies to any other heavily politicised scientific debate, including the nonsense about creationism. As the eminent biologist Francisco Ayala says in his book about evolution, it does not really matter for science if creationism is taught in schools or whether anyone thinks evolution is a conspiracy, because research in evolution will always continue to advance our understanding irrespective of policy. Biological research on homosexuality will continue oblivious to the debate about gay marriage. Research on the benefits of stem cell therapy will continue oblivious to whatever veto the President enforces. Science will continue to thwart the contentions of conservatives about life beginning at conception. Science does not and will not care about the vagaries of politics and spin. And the heart of the reason for this inexorable flow of science is that while politics is about the affairs of humans, science is about factual truths about the world. Its course may be temporarily modified or even stopped in the rare circumstances where unreason triumphs over all (such as in the trial of Galileo), but we can be more than rest assured that since discovery is a process inherent in the history and future of the world, this process will never ever abate. Not just this prize but all vindication of climate change is a vindication of the character of science which will always progress, and we should be thankful for those scientists who keep on quietly working behind the curtains on this progress.

So there is it; the first Nobel prize for climate change. In my eyes, the biggest vindication more than anything else has been about the science. People should yet again be convinced now that the science, with all its uncertainties, is still founded on a solid basis, and this in fact goes to the heart of understanding the scientific process itself. Let's hope that the prize causes even more public awareness than before, especially on an individual basis. Combating climate change will involve changing human nature a little, and that seems impossible. But as Spencer Weart says in his excellent book on global warming, CFCs provide a good example of how humans can change deeply-rooted practices and profit making in the face of impending problems. Global warming is a bigger problem. It will just take bigger efforts. I don't see why we cannot do that.

Previous posts related to global warming and climate change: 1 2 3 4 5 6 7 8

Interview with Brian Shoichet: aggregation-induced inhibition

Ok, now that we have gotten past the Nobel mania (or maybe not; go Somorjai), we can hopefully come back to real life. I was reading an interview with Brian Shoichet, who is one of the most promising stars in the areas of screening, docking, and structure-based design. He has gotten his fingers in many pies, both computational and experimental.

However, it was somebody's comment about the pharmaceutical industry thinking that "Shoichet deserves a heroes prize" that got me looking at his work, and I quickly learnt the reasons for that quote. As we all know, one of the biggest or perhaps the biggest problem facing HTS in industry is false positives. A lot of times, molecules that are found to be active in an assay fail to be active later. If industry could weed out such nuisances ahead of time, a lot of time, money and energy could be saved.

Shoichet, after a lot of interesting initiation and investigation, came up with one simple reason for why molecules may be showing false colours; because they form colloidal aggregates that somehow inhibit the proteins in the assay. If these are broken up say with detergent, the individual molecules no longer show activity. Thus, a relatively simple physical phenomenon is responsible for these molecules showing false activities. Such molecules were detected in earlier assays by some characteristics, mainly very steep dose-response curves and flat SAR; changes in structure usually causing very small changes in activity. They are also often promiscuous inhibitors. But nobody knew what was exactly happening and all the analysis was post-"mortem".

The first step in Shoichet's lab was the elucidation of this aggregation-induced inhibition. The aggregation can be detected with dynamic light scattering (DLS). The more challenging and useful step is to be able to come up with a list of chemical scaffolds that are likely to show this phenomenon, so that one can watch out for them beforehand. Before that, one would also need to know the exact mechanism of aggregation-based inhibition. In case of some molecules, there is some structural correlation, flat aromatic dye-like molecules being prone to aggregation for example by stacking. But many other scaffolds seem more diverse and at first glance show no common functionalities. Ths phenomenon is linked by common physical forces, not chemical ones. The details are not known but continue to be worked out.

Shoichet's lab continues to make progress, and he has recently come up with a screen for detecting such aggregation-based inhibitors (DOI: 10.1021/jm061317y). There are two major conclusions from the study; first, that breaking up aggregates with detergents can be a good way of identifying them, and secondly that aggregation may be a much more common phenomenon for false positives in screens than was thought before. This fact may be extremely significant for industry and could potentially save a lot of time, money and labour beforehand.

In other quite different work (DOI: 10.1038/nature05981), Shoichet also made the cover of Nature, when he used docking and structure-based design to predict the function for an enzyme whose function was unknown, based on substrate docking and analysis. The strategy used was quite clever; docking thousands of high-energy forms of metabolites rather than the metabolites themselves to know which ones would optimally interact with the active site. In this particular case, the "optimum interaction" pointed to a deamination, and the protein of unknown function indeed experimentally turned out to be a good deaminase.

All in all, a very promising chemist and I believe one to watch out for. Unfortunately, the interview itself is published in the journal Assay and Drug Development Technologies, not one which libraries usually subscribe to (I got it through ILL). But here's the DOI anyway (DOI: 10.1089/adt.2007.9996)

Also, again, check out his Colbert-style interview on youtube.

Ertl gets the Nobel, but Somorjai?

And the prize was awarded to German physical chemist Gerhard Ertl for his study of reactions at surfaces. The prize seems well-deserved, but it also seems to be awarded for the general field of surface chemistry, which leaves me (and many others I think) very surprised to say the least that Gabor Somorjai did not share it, especially also considering the fact that the two shared the Wolf Prize together. To my knowledge, Somorjai has been an absolute giant in the field. Compellingly weird.

Well, at least the prize went to a bonafide old-fashioned "chemist" this time.

Addendum: Thinking about it more, I think the Nobel Prize committee really blew it this time. This is because Somorjai is really THE obvious and preeminent candidate for a general prize in surface chemistry. He is heads and shoulders above everyone else in the field in this regard. In this particular situation therefore, the exclusion is glaringly obvious, and I think the committee is going to take a lot of flak for it.

2007 Chemistry Prize: last minute revision

Sorry, but the Nobels have somehow been a minor interest of mine for a long time. I like to know about Nobel stats the way baseball fans like to know about their sports's stats. While I have already listed my thoughts, I also have some personal favourites. These are folks who either work in my field(s) or whose work I have known about for a long time and admired. I also liked the colour of their sports jackets.

Martin Karplus: The doyen of theoretical and computational chemistry, especially as applied to biological problems. More than anyone else he influenced the field

Stuart Schreiber: Great pioneer of chemical genetics. Great life story and again the dominant influence on his field.

J. Fraser Stoddart: Need toys get some from this guy. Sometimes though, his work sounds like too much fun to get a Nobel Prize ...

Ronald Breslow: I have always loved to read about his work. Chances do look a little slim, but a general prize for biomimetic chemistry missing him would be sacrilege. It might miss others though. I am thinking that Ron Breslow being awarded might make both the "pure" and "impure" chemists happy.

Harry Gray: Gentle, unassuming giant of a man. His work on electron transport in proteins is spectacular and I was very impressed when I read about it. Might be a little premature. A general bioinorganic prize might include him and Stephen Lippard. Again, many other contenders, and field may be too general.

Personal favourite fields for Nobel contention: chemical biology, crystallography, medicinal chemistry, computational chemistry, nanotechnology

And Al Gore for detecting anthropomorphic changes in the ozone layer.

In general, I will be happy if anyone who might be called a "chemist" without too much head-scratching gets it. I also realise that the probability of knowing about a correct potential winner would correlate with the number of bloggers in diverse chemical fields who make predictions. At this stage, we have a bunch of bloggers from almost every field of chemistry here who know the biggies in their field who they then can write about for the others' benefit. Thus, one might think that between all our blogs, we have potential "winner space" covered. Nonetheless, last year can only be a sobering lesson, when not a single blogger could predict Roger Kornberg winning. However, we can argue that perhaps it was because there weren't many molecular biologists blogging who could have made that prediction. Since the possibility of a "pure" chemist winning this year seems higher, I am keeping my fingers crossed that at least one of the blogs made the correct prediction.

Now, fight! Till tomorrow.

P.S. Damn...there should be some remuneration for correct predictions.

P.S.2 Last second addition: Albert Overhauser

2007 Physics

This year's prize goes for that-thing-about-which-I-have-heard-but-never-read-up-on. If I have heard about GMR many times but don't know anything about it, it surely must be Nobel-worthy. Compliments to Albert Fert and Peter Grunberg.

Now waiting for tomorrow...

Turning a false-positive into an active

People who deal with molecular recognition are well aware of what difference a small modification to a molecule can make. Just today I was attending a talk by a chemist who binds small molecules to RNA aptamers. He showed an aptamer that binds theophylline with 10,000 fold more affinity by caffeine- a huge difference in binding affinity for a molecule differing by only one methyl.

So it is also for medicinal agents, as demonstrated below for an example from the cited study. People who do screening must always have this nagging doubt about false positives; what if there is only a slight modification to a false positive that will convert it into an active?



Bill Jorgensen's group has done a similar study for an anti-RT HIV inhibitor. He first did similarity searching with the Maybridge library based on six known NNRTI inhibs of RT. Based on this, he found a couple of molecules in the library which he then docked into the active site of RT using the program GLIDE. Along with the six known inhibitors which scored at the top as binders, he also found one from the library. GLIDE had already been benchmarked by reproducing known crystallographic conformations.

However, when they tested this GLIDE ranked molecule against HIV, it was disappointingly inactive. On the other hand, perhaps, since GLIDE had docked it up there with the known actives, there might be a small modification that one could make to it which would inject some activity in it? Jorgensen's group used a program that they have developed named BOMB, which basically docks a molecule in an active site, and then grows appendages to it to see if it would make a difference in the binding affinity. BOMB tried out combinations of different groups on the phenyl ring of the molecule, scored the resulting structures using its energy function, and finally settled on one particular modified structure- also filtered by logP values and other Lipinski considerations- that eventually gave an IC50 of 300 nM. Not a fantastic number, but good enough to pursue as a lead.

Also noteworthy in the paper is a short discussion of another publication where a similar structure was published. According to the authors, the other authors assayed the wrong compound. Heh.

Reference:
From Docking False-Positive to Active Anti-HIV Agent
Gabriela Barreiro, Joseph T. Kim, Cristiano R. W. Guimarães, Christopher M. Bailey, Robert A. Domaoal, Ligong Wang, Karen S. Anderson, and William L. Jorgensen
Web Release Date: 06-Oct-2007; (Article) DOI: 10.1021/jm070683u

2007 Medicine Nobel

Knockout mice...now why didn't I think of that in my prediction post? Seems at least one of them was explicitly a contender for the prize even in 2004 as considered by Nature.

Miles to go before...

A recent and highly promising trial of an HIV vaccine has failed and shown depressing results. This setback reminds us of how complex a problem HIV/AIDS is, with so many daunting scientific, economic, political and sociocultural ramifications...

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