Friday, 29 March 2013

07:43 – I got email from Paul Jones yesterday afternoon shortly after I’d finished reading this article: X-Ray Structures Of Everything. Without Crystals. Holy Cow. As Paul said, if this technique holds up, it changes the world.

And you can be sure that we’ll soon know just how well the technique holds up. Right now, this morning, other scientists are attempting to reproduce these results in thousands of labs all over the world. I asked Paul if Wake Forest University had what he needed to test this technique. He replied that his only concern was that he didn’t know what computational resources would be needed and if WFU had access to them. If this is for real, and there’s no reason to think it isn’t, structural analysis of molecules, possibly including proteins, has just entered a whole new world. The implications are staggering.

How staggering? When I read Derek’s post, I literally checked the date to make sure it wasn’t April 1st.


50 thoughts on “Friday, 29 March 2013”

  1. No, Nobel prizes are reserved for important people who make Earth-shaking contributions. People like Al Gore, Barack Obama, and Yasser Arafat.

  2. Not in chemistry.

    As Derek said, Nobel Prizes have been awarded for less.

  3. We need to add the Nobel Prize to the list of worthless awards like Olympic records, pro sports scores and records, the Pulitzer, high school and college grades, etc., etc. It all means diddly-squat. For someone like me who’s watched the literary Nobel awards over the years it is so completely a joke as to beggar belief. In fact, there really has been no one in literature worthy of receiving any kind of prize anyway since the Nobel was instituted, unless the intent in that field was always to award it for mediocrity and political hoss chit.

  4. I completely agree for the non-STEM awards. But the latter are for real, and are not awarded for trivialities.

  5. Yes, I thought I had implied that but should have made it clearer. The non-STEM awards are mostly bull-chit.

  6. I had a cold chill reading the paper. The only way it doesn’t change the world is if it is an outright fraud.

    As said above, the STEM Nobels are the real-deal. They’re not necessary for determination that someone/something is pretty damned amazing but they are sufficient. I can’t off the top of my head think of anyone who won one that didn’t make significant and pioneering contributions to their field. I can think of a lot of folks who made similar and didn’t win – no one would argue there isn’t any politics (and luck, be sure not to die too soon) involved.

    Given what I do, I’m biased, but I’m almost of the opinion they should come up with something else for this. Let these guys hand out the Nobels for the rest of their lives. Rename chemistry for them.

  7. For the Nobels awarded in literature since the beginning there are perhaps four or five names who belong there; Kipling, Yeats, Eliot, and Faulkner. That’s about it. Over a century. If it went back that far, one could easily add another dozen from each of the preceding centuries to about 1500.

    Of course I’m prejudiced heavily in favor of those writing in English as their native language. My bad.

  8. Yes, when I made that post this morning I was trying to come up with a comparative that wouldn’t sound so hyperbolic that non-scientist readers wouldn’t discount it immediately. What I almost said was this technique has the potential to do for chemistry what the microscope did for biology, but people wouldn’t have believed that.

    It’s early days yet, and we’ll soon know a lot more about how applicable this technique is to other matrices and other molecules. From reading the paper, I don’t think there’s a lot of doubt that this is likely to work on nearly any small molecule. I just hope that it’s usable with macromolecules like proteins. (The issue there is that the matrix itself may denature the protein molecule, changing its conformation.)

    But even if there are limitations, this technique gives us a window on molecular structures that could only have been dreamed of the day before yesterday. And I have faith that, if there are limitations, smart people will figure out how to get around them. This really is seminal.

  9. http://pipeline.corante.com/archives/2013/03/28/xray_structures_of_everything_without_crystals_holy_cow.php

    I have read this article three times now and still do not understand it. I need the layman’s version of the laymans version for this.

    This is why I like having four PhD engineers work with me. I can go to all four individually and get each to explain a portion of the item in question. Then I can pick and choose and get a glimmer of what is going on. I really miss the guy who worked with me for 30 years as he fully retired three years ago. He could give the best explanation of all.

  10. [snip] since the beginning there are perhaps four or five names who belong there; Kipling, Yeats, Eliot, and Faulkner. [snip]

    I would add Solzhenitsyn, Churchill, and Joyce to your list, with Joyce being the screaming omission from the Laureates.

  11. No offense, pcb, but I would not add those guys; I love all three but not as much, and find Joyce overrated a bit. Churchill wrote masterly English but as a historian not at the level of Gibbon and Macaulay. The late, great and very brave Solzhenitsyn should have got the Nobel Peace Prize instead, for revealing the depths of evil and depravity in his homeland. To no avail, sadly, for too many people in the West and too many back there who still revere Koba the Dread.

  12. Churchill wrote masterly English but as a historian not at the level of Gibbon and MacCaulay.

    Churchill was too busy making history to write great works. I am still amazed that his split of the Middle East has essentially lasted this long. Of course, even he did not expect the formation of Israel and even fought against it. If Iraq splits into three countries later this year or next as I expect then many country lines will be redrawn over the next 5 to 10 years. And maybe even a war or two or ten (can you say Kurds?). Hopefully the USA will stay out of that nastiness this time (but I do not count on it).

  13. I have read this article three times now and still do not understand it. I need the layman’s version of the laymans version for this.

    I was going to take a stab at this, but I’m sure Paul Jones would do a better job of explaining it. (He is, after all, a professor of organic chemistry.) I’ll ask him to reply, but keep in mind that this technique is applicable to the entire field of chemistry, not just organic.

    Oh, hell. I’ll take a quick stab at it until Paul gets around to giving you the real explanation. Here’s the layman’s version:

    Even large molecules are incredibly tiny, and having the ability to actually “see” them would be extremely helpful to understanding all sorts of things. But we see only by visible light, and the wavelength of visible light is much too long to resolve detail in such tiny objects. (Think how hard it would be to measure, say, the thickness of a hair using only a yardstick.) X-rays have much shorter wavelengths than visible light, short enough to resolve detail in molecules. But we can’t see X-rays.

    Enter X-ray crystallography, where scientists grow crystals of the compound they want to visualize and then blast X-rays through them. Much as a glass prism refracts light and produces a characteristic pattern, crystals refract X-rays to produce characteristic patterns that vary according to the structure of the compound that makes up the crystal. (Originally, these patterns were captured on X-ray film; nowadays, electronic detectors are used.)

    But the problem is that not everything is easy to crystallize. In fact, most organic compounds aren’t easy (or even possible) to crystallize. No crystals = no X-ray crystallography. And, with some exceptions, the larger and more complicated the structure of the molecule is, the harder it is to get it in crystalline form. Crystals are matrices, so many simple ionic compounds crystallize easily. Conversely, big huge organic molecules are complex conformationally, so those molecules tend not to form matrices easily, if at all. So if you want to analyze the structure of an organic molecule that wants to form an amorphous sludge instead of nice crystals, you’re out of luck. Or you were until yesterday.

    This new technique puts individual molecules of the compound onto an incredibly tiny matrix, allowing analysis of nanogram quantities of the material in what amounts to amorphous form. In effect, we’ll be looking at a “crystal” that comprises one molecule.

    What everyone wants the answer to is how generally applicable this technique is. My guess is that the answer will depend a great deal on the interactions between the material that makes up the substrate and the individual characteristics of the analyte molecule. For example, proteins are notoriously easy to denature (change the structure of), and it’s possible that the mere fact of a protein being adsorbed onto the substrate will cause unpredictable changes in its conformation. Or it may not, depending on the particular substrate material and the particular protein.

  14. The late, great and very brave Solzhenitsyn should have got the Nobel Peace Prize instead, for revealing the depths of evil and depravity in his homeland.

    He certainly deserves the Nobel Peace Prize, but lumping him in a group with most of the other recipients of that award is to slander his accomplishments. How many Nobel Peace Prize recipients since Lech Walesa actually deserve the honor? Did Lech Walesa do more to deserve the prize after receiving that honor than before receiving it?

  15. No argument from me on that, Dave B.

    Nice job of ‘splainin’, Bob. Even I get it, mostly.

  16. Thanks Bob. This is why many of us come here. There are so many subject matter experts on a lot of stuff who can put things in layman terms.

  17. Oh, hell. I’ll take a quick stab at it until Paul gets around to giving you the real explanation. Here’s the layman’s version:

    Thank you! I understand that better now. OK, somewhat.

    This is actually interesting to me as I am contemplating adding support for solids in our software package. We support three phases right now: vapor, hydrocarbon liquids and aqueous liquids. We do allow the user to say they have solids but we just throw the solids into the aqueous liquid phase and never allow the solids to transform into a liquid or vapor. Or vice versa.

    So, I have been reading up on solids formation and crystallization is all over the map. Time is a big factor, seed crystals can be important and many other factors contribute to it (deposition, etc). Predicting formation of solids is not nearly as cut and dried as vapor to liquids or vice versa.

    Formation of solids is important in our business due to water ice, solid co2 or hydrates formation in pipes or columns. We predict all three but just as a warning to the user. We do not actually take the heat of fusion into account for our thermodynamic calculations nor in our phase equilibrium. Someday…

    Again, thanks for the layman of the layman explanation.

  18. Wow, Lynn, that sounds like an interesting program. You wouldn’t need a remote consultant, would you? Beat me, whip me, take me away from working on yet another government web application to more efficiently transfer money from the productive to the unproductive.

  19. Sorry, none needed at this time. BTW, here is the software that I write and peddle: http://www.winsim.com/

    And no remotes! If I cannot attach the workstation ankle bracelet then I am just not interested. I tell you, if I get one more extraneous potty time request…

  20. Heh. No problem; I wasn’t especially serious. And I’ve dealt with control-freak bosses before, down to monitoring the duration and frequency of bathroom breaks. (Though, IIRC, that boss didn’t monitor smoke breaks, probably because he was a smoker.)

    Also, to be honest, working on BS government contracts is my way of going Galt. I don’t have the assets to simply stop working* so I need to do something to keep the roof over our head. BS government contracts lets me do that while contributing nothing to the economy.

    * Thanks mainly to my wife. Before this marriage, I had a year and a half until my mortgage was paid off, and the other two apartments in my house were occupied and paying the mortgage and taxes. No other debt. Now, eight years later, I’m working my ass off, barely keeping the bills paid, and up to my ears in mortgage.

  21. “…Now, eight years later, I’m working my ass off, barely keeping the bills paid, and up to my ears in mortgage.”

    Ditto.

    Remind me again why we get married.

    And gay people want some of this, too?

  22. I paid off my mortgage early last year, only to get it back when I bought a new car. I’m paid off now (again) and am wondering what to do with all the extra moolah ($21k per year). Perhaps I should get married… 🙂

  23. For those not fully understanding the importance of the x-ray crystallography paper, here is an example of how big a deal this is. To get the structures of these compounds, you want really high quality crystals. So high quality that experimenters are willing to wait years (and pay millions) to get time on the International Space Station to grow their crystals in microgravity and have them brought back for analysis.

    Lynn: did you see that the Japanese are setting up a pilot well to produce natural gas from undersea methane hydrate ice? A big win if they can do it economically. Also, a friend of mine is a PhD researcher at Shell in Houston. His specialty is turbulence, and he does work on slowing waxy buildup in producing wells.

  24. There are some obvious limitations to the idea of putting molecules into an existing crystal to do X-ray crystallography on them. For one thing, they have to be small enough to fit into the gaps in the crystal. They have to interact with it strongly enough to be bound in a consistent position in each gap, but have to interact weakly enough that they don’t clog the pores in it and prevent more from coming in. (If they fill gaps in a crystal, but end up in random orientation in each gap, it won’t be of use: X-ray crystallography requires a uniform array. Well, probably you can do something with the data if each added molecule ends up in, say, one of five orientations, but at the least it’ll add noise to the result.) If this technique becomes established, a considerable art will probably grow up around the choice of crystal to use to get a good picture of a target molecule. Or, in the case of too-strong bonding, how to figure out the right combination of heat and time to get the target molecule to diffuse in sufficiently.

    Still, sounds like nice work.

  25. I paid off my mortgage early last year, only to get it back when I bought a new car. I’m paid off now (again) and am wondering what to do with all the extra moolah ($21k per year). Perhaps I should get married…

    Dude, that costs way more than $21K per year…

  26. No, after an evening and morning of being bitched at by my wife, I’m not laughing. I’m weighing the relative merits of having her deported and arranging an unfortunate accident.

    But it’s not just me she’s bitching at — she also reduced the five-year-old to tears last night (good job!) and was screaming at her mother last night. You’d think that, in 35 years since puberty, she’d have learned to deal with PMS, but you’d be wrong.

  27. But it’s not just me she’s bitching at — she also reduced the five-year-old to tears last night (good job!) and was screaming at her mother last night. You’d think that, in 35 years since puberty, she’d have learned to deal with PMS, but you’d be wrong.

    I’m no expert, but 35 years after puberty, I don’t think PMS is the problem. I think it’s more likely the mentalpause.

  28. Nah, I can afford to get married. That $21k is just the icing on the cake. And I’m not planning to marry a checkout chick. I wanna marry a rich, nubile young dentist.

    Oh, there’s a redundancy there: I wanna marry a nubile young dentist.

  29. SteveF wrote:

    “I’m weighing the relative merits of having her deported and arranging an unfortunate accident.”

    The former would involve lawyers, so I’d advise the latter.

  30. Oh, there’s a redundancy there: I wanna marry a nubile young dentist.

    Nubile young females tend to be fertile. This causes nine months of pacing back and forth nervously followed by 18 years of sleepless nights. And then you finally get some peace and quiet when they go off to college. Unfortunately in the modern era, a college education doesn’t pay for itself unless one is very wise, and the kids now move back in afterwards.

  31. Lynn: did you see that the Japanese are setting up a pilot well to produce natural gas from undersea methane hydrate ice? A big win if they can do it economically. Also, a friend of mine is a PhD researcher at Shell in Houston. His specialty is turbulence, and he does work on slowing waxy buildup in producing wells.

    “Economically” is the key word here. Most people do not know that the Gulf of Mexico (and all other DEEP bodies of water) are covered with three to five feet of methane hydrate ice below 2000 ft. Natural gas forms a hydrate ice with water at 1000 psia and 63 F.

    Shell has a million projects going on. I had a friend of mine take early retirement a couple of years ago when the Shell USA president figured out that they were working on a project to produce Rocky Mountain tar sands oil 3000+ ft down in the earth using electric rectifiers. He did a back of the envelope calculation during their proof of concept meeting (over 100 people in it) and found out that they were going to need over 1,000 nuclear power plants to produce the oil. The project got canceled that day.

  32. “…and found out that they were going to need over 1,000 nuclear power plants to produce the oil.”

    I advocate building thirty a year for thirty years in this country; that would give us 900, anyway.

    Sorry about yer bad day, SteveF; I have several similar anecdotes from the past fifteen years which involved both fembots at this house that would make yer hair stand on end. One involved someone claiming that I threatened to kill them and another one involving potential use of firearm/suicide/homicide. Neither was my fault whatsoever but there I was. Lots more where those came from. Why my facial hair is turning white.

  33. No, after an evening and morning of being bitched at by my wife, I’m not laughing. I’m weighing the relative merits of having her deported and arranging an unfortunate accident.

    But it’s not just me she’s bitching at — she also reduced the five-year-old to tears last night (good job!) and was screaming at her mother last night. You’d think that, in 35 years since puberty, she’d have learned to deal with PMS, but you’d be wrong.

    Wow. Sorry to hear that. Is there anyone that she can go talk to? In my life, I would advise her to seek council with the wife of one of the our Elders. She sounds really unhappy about something.

  34. It has been a whirlwind since we put the old house on the market Thursday morning. About 21 showings that we know of and 10+ offers. We just signed the offer that was all cash for $10K over the asking price. Blew me away and a great blessing. Poppa needs a new layer of asphalt on the gravel entrance road going to our office building!

    The buyer is a Chinese? couple moving here to the Land of Sugar in the Great State of Texas from the state of Kalifornia. Of course, I stipulated a few things in the purchase contract that they must agree to. And we have to get to closing on April 22 (they wanted May 15).

  35. Very nice, Lynn; we have seen houses sitting lifeless on the market here in Nova Anglia for years at a time, with no viewings, let alone offers. Even so-called short-sales take many months or even years. We were lucky to get ours at the price they had for it; but it seems like even with this bad real estate market continuing up here (except for very high-end luxury properties, natch) owners won’t come a dime off their prices. Even while they’re “underwater” with their mortgages.

    Oh, and it still took us a full year of hassles with the VA and the mortgage people to get in here finally last October. On TOP of our regular work schedules and multiple family crises.

  36. South Texas is very hot with lots of jobs. The Eagle Ford shale area is going nuts with over 300,000 new jobs there in the last couple of years. And the amount of people moving here from Kalifornia is simply amazing. Of course, in many cases their jobs are moving here so they have no choice. I am hoping that they do not bring their west coast liberalness with them too. I like The Great State of Texas the way it is now, even if we have to secede in order to keep it.

  37. She sounds really unhappy about something.

    Nah, just PMS. Every month for the past eleven years, except when she was pregnant. And it comes as a surprise to her every month — apparently Chinese women of her generation never learned to mark a calendar. But wait, it gets worse: from talking to several Chinese country folk (ignorant farmers, basically) I got the impression that the commoners of maybe 40 years ago didn’t understand when a woman was fertile. Sheesh. No wonder they’ve got over a billion people.

    Oh, and the same went for Indian villagers up until a few decades ago, and maybe even today. Sheesh again. Yep, India has over a billion, too.

  38. I am hoping that they do not bring their west coast liberalness with them too.

    Good luck with that. Californians, New Yorkers*, Illinoisances, and Massachusettsians flee their crapped-out and crapped-up states and bring their crap wherever they go.

    * Though I live in NY and mostly grew up here (to the extent that I grew up, that is) I draw a sharp line between upstate and downstate. Upstate has a mix of social and political views, but we’re overwhelmed by the gutter scum of the city. Same went for Minnesota when I lived there. Possibly the same for Massachusetts, though I think even western MA is more liberal than upstate NY.

  39. Mrs. OFD grew up in Glens Falls, and has told me there are two versions of “upstate” in the Vampire State; the one held by people in NYC and Long Island, which to them is anyplace twenty or thirty miles outside their area. And the other one, sometimes called “the North Country,” which is quite a bit further out. The Albany area to her is not “upstate.” And a whole different ballgame again out in the western paht of the state, too. The minor-league baseball team out there is the Batavia Muckdogs, who sometimes play our Vermont Lake Monsters and in Maffachufetts the Lowell Spinners.

    Western MA is librul to the extent of the wealthy Dems and inta-leck-shuals who bought properties there from The Good War on and now infest the place. The Commonwealth as a whole is pretty much librul Dem, although a few right-wingers still survive here and there, kept as museum pieces, circus exhibits and curiosities. The state generated a whole ton of misery through its export across the country of its Calvinist beliefs and ideologies and the misery continues. I was born and grew up there and am descended from those same Pilgrims, Puritans and Quakers, but have learned the errors of their ways, praise be to God. And have moved away, to yet another librul Dem state, but there’s more fellow right-wingers up here and more Catholic gun nuts. Again, thank God.

  40. Steve F wrote:

    “Possibly the same for Massachusetts, though I think even western MA is more liberal than upstate NY.”

    In 1972 Mass was the only state Nixon didn’t carry, and of course, after Watergate became known, they displayed bumper stickers “Don’t Blame Me, I’m From Massachusetts”.

    Western Mass was represented by a Republican, Silvio O. Conte. He was re-elected in ’72 but his district voted for McGovern. The only district in Mass that voted for Nixon elected a Democrat. Some other districts in Mass elected Republicans, and Edward Brooke, a Republican, was also re-elected to the Senate that year from Mass.

    The thing that surprised me was that Reagan carried Mass at least once, and he was to the right of Nixon.

    There. I bet you didn’t know all that… 🙂

  41. I remember in 1976 reading in Time that Gerry the Dope was as far right as the country would tolerate, and that Ron was too far right to be elected. I also, would have voted for him if given the chance, but some of his advisers were scary and he ran up big deficits.

  42. Our last decent president was Grover Cleveland.

    And as for the various regions in the Vampire State, Mrs. OFD informs me that “upstate” is basically the Adirondacks, from Glens Falls up to Massena and over to Watertown. The Albany area is “The Capital District.” And has a lot of the same types of rumpswabs as NYC and Long Island. Present company radically excluded, of course.

  43. Our last decent president was Grover Cleveland.

    Which time?

  44. Bob pretty much nails it (diffraction, not refraction). And Norman provides some caveats and cautions.

    X-Ray analysis today is an order of magnitude better than when I was a grad student. More powerful x-ray sources, more sensitive detectors and much, much more powerful/fast computing power makes it so. We get structures today in a day on really crappy looking crystals where 20 years ago we needed a big, perfect crystal and a few months.

    But, still, you need a crystal and those are hard to come by. Growing crystals is more art than science. I spend a fair amount of time yelling at students not to be too rational in trying to grow them – try everything.

    The new technique takes an existing crystal, with known structures and absorbs the small molecule. If the small molecule fills the crystal voids with some regularity, the change in the diffraction pattern can be used to calculate its structure. Getting that information can be very difficult, though not impossible.

    It is very unlikely that there is any large crystal that will work in all cases. I suspect a set of crystals will emerge that form a basis set that will work for, say, 90% of small molecules. It would be nice to come up with a way of detecting regularity of the interaction between small molecule and host without having to diffract x-rays.

    What really makes this exciting, to me, is how little sample is required. Give me 100 mg of a compound and I can figure out its structure without x-rays. Give me 10ng and I’m screwed. I can get a mass spec and that’s it.

    The method as it currently exists (one assumes it will get better) isn’t good enough for things like bond angles, distances, etc. as it just isn’t accurate enough. But for connectivity (of the atoms), including stereochemistry (there are two different ways to put four different groups around a tetrahedral atom, for instance), this will do nicely.

    Macromolecules will be a challenge. Much bigger voids necessary – and crystals with very large voids have a tendency to collapse.

  45. Yeah, I dithered about that, but I figured most people understood refraction from watching a prism make a rainbow, while fewer would understand what I meant by diffraction.

  46. “Which time?”

    Both, the first more so than his second term, where he did his best under circumstances beyond his control.

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