A nerdy post after such a long break. Sorry

Zinc fingers is typically a domain of about 60 amino acids that fold around one or more zinc ions and is found in over 400 eukaryotic proteins, many of which are involved in the regulation of gene expression and in the maintenance of chromatin structure. Zinc fingers typically show a C4HC3 signature (four cysteines, one histidine, three cysteines) with characteristic cysteine spacing and with additional conserved residues, most notably a tryptophan or other aromatic amino acid preceding the final cysteine pair. Studies have suggested a role for zinc fingers as nucleosome interaction determinants. However their functions are still elusive and controversial, as a variety of functions have been suggested, including phosphoinositide binding and E3 ubiquitin ligase activity. In addition to their role as a DNA-binding module,  zinc finger have been shown to mediate protein-protein and protein-lipid interactions as well.

What about the electrostatic surface properties of zinc-finger domains? Here an example with the models of the 4 zinc-fingers of one of the histone methyl-transferase I’m working on. On the figures, blue is positively charged, and red is negative. The large positive (blue) area will bind to the DNA. But, on the other face, there is room for binding to some positively charged partners. Fascinating!

I recently came across this excellent commentary by Brian Matthews on the 5 (five…) papers Chang et al. retracted back in 2006. For those not familiar with X-ray crystallography and the Changs papers withdraw from leading scientific publishers, I give you a bit of explanation. X-ray crystallography is the gold standard in structure determination and it uses a crystal of pure molecular specie(s) shot through an X-ray beam. If the crystal is good, the electron clouds of the atoms diffract the x-ray beam. By recording various diffractions images, one can compute the electron density inside the crystal and trace (build) the molecular specie(s) in it. Sound simple enough? actually no. I’m not talking here about the maths and physics involved and the phasing problem. The essence of  X-ray crystallography is to solve the phase problem leading to having “good” and “reliable” maps of electron density.

What happened to Chang et al., is that they were working with some wrong electron density maps because of a gross error made early-on during the project pipeline. The culprit was an in-house data reduction program that switched critical column of data. Because of this error, they build/trace various proteins with the “wrong” hand.

Brian Matthews commentary is a solid X-ray crystallography 101 lesson. A lot have been said and written about Chang et al. mistake and their consequences. But, Brian Matthews point out that nowadays we are seeing an ever-increasing use of “black-box” procedures for structure determinations. The rapid development of easy to use X-ray crystallography softwares along with massive computing power render the structure determination fairly easy for one with limited X-ray crystallography knowledge. Solving a structure can be fairly straightforward but it can easily become a tricky task. In any cases but especially in tricky cases, one needs to be extremely cautious about the validity of the maps. Brian Matthews gave us a great lesson about the various checking we all should do when dealing with problems encountered by Chang et al.

X-ray crystallography is like anything else, it is an art. It requires experience, failures, learning from failures and constant knowledge update. Like everything else in Science, it is a grave mistake to assume that we master all the whereabouts of a technology/methodology. I guess, Chang et al. learnt it the hard way. However it raises another question: Shall we seek advice from a peer to help solving a problem in case of dealing with a very hot project? All the 5 retracted papers were all hot projects…

The take home message from this is to be über-cautious and don’t take nice looking maps for granted…

Already 40 years…already 40 years that what is perhaps the greatest achievement of mankind, led to having the very first earthling fooling around on the moon. It was the ultimate achievement of one entire nation fulfilling J.F Kennedy promise back in 1961. A 3 stage-programs (Mercury, Gemini and Apollo) and billions of dollars spend, led not only to having men on the moon but also great scientific progress and to an extraordinary technological leap forward, skyrocketing the entire world into today’s reality. We can thank the cold war for fuelling a frantic space race between the USA and USSR. But the legacy of such space race is massive and everywhere in our today’s life.  Going to space and to the moon required a handful of technology that we didn’t have. Where to start?  The benefits of the space program are virtually everywhere.  For instance, home insulation, cordless power tools appliances, LED light, laser, lightning protection, shades, robotic, portable breathing system among many others. UNIX is also a spinoff of the space program.

Most of all, the space program and the most of all the lunar explorations by Apollo 11 to 17 (except 13) provides an extraordinary reservoir of dreams for billions of earthlings…for decades. Which kid doesn’t want to be an astronaut as some point? Which one of us didn’t say  ”I wish it was me on that freaking Space shuttle even if I have to throw-up during the 15 days of the mission? right?

As for myself, that brings me to get an airplane pilot license and to apply to the European Space Agency astronaut selection program in June ‘08. Luckily, I got selected and I touched for a little bit of what being an astronaut could be while having my butt kicked during the tests in Germany.

Apollo 11 Landing anniversary must remind us that we should not stop investing in great and ambitious programs such as the space exploration. On another level, the Concorde program brought many technical achievement that are not only in use in all nowadays airliners but in all vehicles, computers, etc…. Just as a reminder, at the time of the Concorde program, only very few military aircraft were able to sustain mach 2+. Concorde was able to comfortably cruise at mach 2.02 for 2+ hours at 60.000ft…advanced military aircraft territory.

To realize how great it was, let’s imagine that the mighty SR-71 blackbird was probably the only aircraft able to overtake the Concorde during a transatlantic crossing without refueling. The legend wants that one day somewhere over the Atlantic an SR-71 blackbird flying at mach 3 was overtaking a Concorde cruising below at mach 2. The crew of the blackbird suddenly realized that they were sweaty, tired and strapped in a rather uncomfortable space-suit, breathing cold and dry oxygen while just below, 100 passengers flying at twice the speed of sound, where having foie gras, caviars and delicious Champagne…In a similar manner of the Apollo program France and UK spend billions to make Concorde a reality.

As today’s economy is going side-ways, it is the time to massively invest in very ambitious programs during the coming years. Tomorrow’s world will thank us later.

I just come back from a very pleasant trip to South-Korea where I visited the Kyungpook National University (KNU) in Daegu. A very nice and inspiring trip overall. I met great individuals both at the university and off-campus with whom I had very very interesting chats. I definitively need to spend more time in Korea. Unfortunately, I haven’t seen much of it because of a too short of a trip.

A cool picture of the hexameric enzyme Quinolinate Phosphoribosyl Transferase (QAPRTase) of S. cerevisiae showing its electrostatics intimacy. Blue are +, red and – and the field-lines are displayed. The very interesting thing here is that the field-lines are rooted from each active site outside area (6 of them). I used ABPS for the electrostatic calculations and VMD 1.8.7-alpha to visualize. The substrates Quinolinate and PRPP are basically sucked-in into the active sites following the electrostatic field-lines. It is an obvious result, but those kind of analysis are cool don’t you think ? So…what about the release of the product synthesized ?

Well I have been very busy lately. I went to France for a couple of tenured-track faculty interviews at the CNRS national labs. Overall, it was an interesting experience. I had a pleasant time with the committee 16 “Chemistry for living organisms and medicinal chemistry. Design and properties of compounds of biological interest”. However, my research proposal was a little bit out of scope for this particular committee unfortunately. But overall, it was good talking with this committee.

A week after I was interviewed by the committee 21 “Molecular and structural features underlying biological functions” and the fun began. I found what I hate the most among tenured-track faculties in France: very narrow-minded person, rude for no reasons, not listening to me at all…well pathetic people for most of them. The icing on the cake was when I was explaining my current project in the US about the molecular modelling of protein (funded by the NIH). I am a crystallographer but I am currently doing protein-modeling stuffs. The committee was obviously a group of hardcore old-school experimentalists and they violently told me that it is bullshit..meaning protein modeling is bullshit…. should I laugh now and tell them they are wrong, narrow-minded and stupid or should I save that for latter…My current research in protein modelling is all about models-validation with an experimentalist (X-ray crystallography) point of view!! The committee 16 was pleased with that, so why did you guys from the 21 didn’t get that?? Maybe I wasn’t clear enough. That’s must be the reason (sarcasm). 

Some of my friends who went through this hassle before me in different committee experienced the same fun. Awesome ! In my case, I guess it was just a bad experience on that one. But, don’t get me wrong. Working in France at a CNRS or INSERM lab is cool. You don’t get much salary compared to the US, but you do get plenty of vacations, a stress-free working environment (please don’t tell me you are under stress right ?) and if you move your ass a little, you can get some grant money to do good research. But you might end-up working with some people with this typical French narrow-minded mentality where they expect you to fall into a specific old-fashion category. If you are a little bit too atypical you are over.

This being said, it leads me to think: What the heck am I applying for positions at the CNRS or INSERM anyway? right ? Do I want to work with this kind of people? I feel so much better working in the US in every possible ways. Then now, ask yourself why so many of us leave France after graduating with a PhD and never come back in the French academia system ?