There are many cool things that can be done when mixing wet “classical” biochemistry and computational biology/biophysics. The virtual ligand screening is one of those things that fall into the major cool category. Nowadays computer have plenty of horsepower that can be put into good use to simulate the binding of libraries of small molecules onto an active site of an enzyme for instance. Following the in silico simulations, the *best* molecules are assessed in the lab for their *experimental* binding/inhibitory properties. In the following video, I used AutodockVina to dock a small subset of 943 compounds into the human SETD1 (NSD1): 20 best docking solutions for each compounds = 18860 docking solutions!

After weeks of ordering lab stuffs, chemicals, equipments, we can finally switch gear and get the research started. Thanks to a grant from the national research foundation of Korea, Masayo joined the lab along with a lab assistant and an undergraduate student. I’m thrilled to see finally the projects taking off. It is really a great feeling. I can’t wait to see the lab accumulate good and solid data. Here a short iPhone video of Masayo taking care of some human gene constructs we got today.

My life just got 10x better. I have been notified that the National Research Foundation of Korea (NRF) will fund one of my project (I’m the sole PI) for the next 3 years with a descent amount of money too. Now, I can hire a tech for 3 years along with a couple of students to work on that project and study the 3D structures of the NSD proteins (transcription co-activators – TCA) along with trying to understand the inter-domain flexibility of TCA during functions.
I’m now seriously thinking of publishing some of my preliminary data.

Here some of the figures of my grant.

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!

Over the last months, I have been monitoring in disbelief the number of “comments-spams ” that hit my website: 4,464 since March 23. Too me, it is way too many for a website that gets an average of 10 legitimate visits per days. I absolutely can’t wrap my mind around the fact that somewhere an army of bots/zombie PC are burning a lot of CPU and bandwidth to vomit a load of nonsense comments on websites…Thankfully, the spam gets caught in powerful filters such as Akismet. So far 99.955% of the comments are junk on my site…It leads to the question: “How much energy can we save if we take down all the spam-servers?, how much bandwidth can we save?

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…