Nobel Notes

Thumbs up to the Nobel Foundation for their decision regarding Ralph Steinman's laureate status. I always felt that the rule was to make sure nominations of those who have passed on were not submitted in the first place. Now, whether or not one agrees with this is a separate issue.

Given that my professional interests are not very immunological or astrophysical, I don't have any particularly incisive commentary about the Physiology/Medicine or Physics Prizes.

A followup to a comment elsewhere - Tom Wainwright passed away in 2007, so unfortunately he would be ineligible for a Nobel. Given that Aneesur Rahman and George Vineyard have also passed on, Alder is really the only "founding father" of MD who would be a possibility.

On the off chance it is a magnetic resonance Chemistry Prize this year, I will not be sarcastic and post "but it's just applied physics! Why are applied physicists winning Nobel Prizes?" I'll actually just write a short blurb on what was so cool about the new laureates' research. (All other fields of physical chemistry being recognized are fair game for such commentary, though.) Read more!

Surely you jest!

So, I strongly recommend everyone checks out this paper -

Accessing protein conformational ensembles using room-temperature X-ray crystallography

- which was just published in PNAS this week. The paper cites a 2004 paper by Bertil Halle (which I mentioned a while back) on the potential consequences of flash freezing and cryocrystallography.

Enjoy! Read more!

No, I am not going to talk about the recent paper on the success of Foldit. Mostly since if you can even get a crystal structure for something, it's probably not agonizingly painful enough for me to work on - as I've said before, give me your disordered, your poorly soluble, your aggregated masses yearning to be analyzed.

Anyway, I wanted to mention this interesting-looking paper:

Binding Leverage as a Molecular Basis for Allosteric Regulation. I haven't had a chance to really dig into the paper, but the idea itself is simple enough - ligand binding can couple to various collective motions in proteins to varying extents, due to which we observe allosteric modulation of enzyme function. There are obvious oversights (one example that they mention in the paper - the lack of attention paid to proteins that aren't enzymes such as signaling proteins of various types), and I'd want to pore through which structures they used in the PDB (e.g., how did they deal with the family of structures that are generated by NMR if applicable). Then again, I usually consider thought-provoking ideas worth the publication, even if a judiciously skeptical outlook may make them seem a little less lustrous. Read more!

As it’s that time of the year again to start speculating about potential Nobel laureates for 2011, I’ve already chimed in at The Curious Wavefunction and left a short note over at ChemBark.

While I’d be pleased to see another magnetic resonance prize (or five), there is a huge name which I’ve neglected, mostly since I was afraid that his time to be recognized had passed, but as he was the Welch Award recipient this year – John Waugh from MIT. Of course, if it were up to me, I bet I could come up with at least half a dozen trios of deserving recipients for magnetic resonance. But anyway…..

I’ve wondered about this earlier and I might as well bring it up again – what about the Kavli Prizes? Currently, they’re awarded for astrophysics, nanoscience, and neuroscience – will see ever see a dual Kavli and Nobel laureate? Or will being recognized with one put you out of the running for the other? Having said that, I know people were predicting someone getting a Nobel for semiconductor nanocrystals, so perhaps if Lou Brus is recognized by the Nobel committee, we’ll see one this year.

Quantitative biochemistry is not giving me quite as much of a headache. Although I'm hardly done with it just yet. I do envision there being an extremely dense biochemistry publication in my future. Speaking of which, back to working up data.... Read more!

A few quick thoughts.

I am still trying to unenviably navigate an n-dimensional parameter space, attempting to optimize the biochemistry for the present bane of my existence in order to get to some proper structural & biophysical studies. It is further complicated that whenever I do seem to devise a plan, something odd crops up in my data in amidst the general experimental madness (remember, if you work with n components, you need to vary one and keep n-1 constant : easier said than done!).

In any case, I stumbled across this interesting paper. Given my innate worrying about structural data obtained under cryogenic conditions, this was right up my alley – utilizing mesoporous materials to confine proteins and their hydration waters, and then using your interrogation method of choice across a range of temperatures without having to worry about the effects of bulk water. I can envision that this would be an excellent way to more explicitly bridge the gap between cryocrystallography and dynamic/functional studies done under more physiologically relevant conditions.

There was a very long back-and-forth over at The Curious Wavefunction this past week. I basically have the opinion that expecting physics to “explain” chemistry and biology is perhaps a bit overly demanding. I mean, it’s not as if all physicists are just waiting to wrap up high-energy/elementary particle physics and then retire, after all! There are still a number of unresolved questions in physics, and as a number of them involve many-body systems, it would only seem reasonable that those are the ones that would likely be of the most immediate application to chemistry and biology.

Now to finish preparing for this inclement weather…..
Read more!

As has been often noted about a number of topics, one’s biases will always skew one’s perspective.

On the one hand, we have this very interesting paper where the authors suggest correlated motions in ubiquitin over a distance of ~ 15 Angstroms (1.5 nm) based on further squeezing information from previously acquired NMR data with the help of computational methods. On the other hand, there is this other very intriguing paper where the authors put forth using gadolinium tags as a way to obtain structural constraints in proteins on the order of ~ 6 nm (60 Angstroms) via ESR/EPR techniques.

In the former, we’re looking at proposed long-distance correlations based on a bunch of relatively weak, short-range interactions (NOEs and RDCs), while in the latter we have nanometer-scale distance constraints being derived from a technique that is well matched to determining distances at the nanoscale. I figure the astute reader can figure where I stand on each given my tone.

Suffice it to say, it’s the reason why I’ve recently developed an interest in ¹⁹F NMR (oh, to work with a nucleus that has a decent gyromagnetic ratio and isn’t as common as protons in biological materials!), for one, as well as metal binding tags for paramagnetic relaxation enhancement studies.

In other news, my resolution for the second half of 2011 is to always try and work in a mention of the Helmholtz free energy into each discussion I am involved in that touches upon thermodynamics, as I think far too many chemists have gotten comfortable in their Gibbsian-oriented world.

I suppose this is one of those “it was bound to happen” things – one of the summer undergraduates who is in my lab at my current institution mentioned that the undergrad biochem lab uses a hexahistidine-tagged protein for overexpression & purification. I of course remember having to prep and subsequently grind up giant amounts of animal muscle to extract a protein in my undergrad biochem lab. I feel slightly dusty.

With that observation, I will call this blog post to an end. Read more!

SAXS And Promiscuity - Or, What Your Biochemistry Text Doesn't Cover.

Glycolysis is one of those things you learn about as an undergraduate (in high school as well, to be fair, but in a good bit more detail in an undergraduate biochemistry course) and – at least in my experience – it was presented as a topic that had already been well-explored and thoroughly annotated. After all, if it hadn’t been, would they have put it down for posterity in a textbook?

Snickering aside, I was pretty intrigued to see the following paper the other day for more than just being another entry in my “clearly, plenty of mechanistic detail was glossed over in my biochem text” list. Basically, the research team utilized a combination of crystallography, small-angle x-ray scattering (SAXS), and computational model to develop a scheme for the mechanism of phosphoglycerate kinase. They propose that the enzyme has a preferred “open” conformation where substrates (1,3-bisphosphoglycerate and ADP) can bind (separated by over 15 angstroms), and then a “closed” conformation, where the domains “fold in” on one another, bringing the substrates together for chemistry and which exposes a hydrophobic patch, which they suggest drives the preference for the “open” conformation. In the supplemental info, they do have some movies for download which make for fun viewing.

It is a nice example of what some in the structural biology field have been pulling for, an integration of high-resolution methods with lower-resolution methods that can provide additional insight into dynamics at the domain scale and above. Just as a representative example of this thinking is the SIBYLS beamline at Lawrence Berkeley Lab (SIBYLS – Structurally Integrated Biology for Life Sciences, where they possess the ability to do both crystallography and SAXS at the same station). They’ve also got a fairly lengthy review linked to on that page that describes the interplay between crystallography, SAXS, and computational methods.

In the spirit of Wavefunction’s link post the other week, at least, I stumbled across this recent paper on stochastic ensembles, conformationally adaptive teamwork, and enzymatic detoxification today. I am still working through the paper, but – given that one of the authors has written rather extensively on atypical (non-Michaelis-Menten) kinetics in enzymes – he is putting forth a new set of organizing thoughts for understanding the unusual substrate binding and catalytic properties of detoxification enzymes (which frequently have multiple isoforms differentially expressed in tissues). These enzymes are not only promiscuous in terms of the substrates they’ll work with, but are also involved in multiple metabolic processes. So it's hardly as straightforward as biochem texts are fond of portraying with those nice, neat flow charts. I have occasionally considered this as a possible reason for all those secondary metabolites in plants that no one can figure out why they're present in the first place - you have a bunch of enzymes floating around in the cells and given enough time, stuff happens. But that is perhaps another post for another day. Read more!