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Wow. I'm floored that computational structural biology work is getting a Nobel. I spent a lot of time reading their papers in grad school...they're totally foun

by timr 13y ago

Wow. I'm floored that computational structural biology work is getting a Nobel. I spent a lot of time reading their papers in grad school...they're totally foundational for the field, but the field is still really young: Martin Karplus' group is behind CHARMM (http://www.charmm.org http://www.charmm.org), which was the first(?) molecular dynamics package (you can think of it as a precursor to folding@home, though it's still under active development, so that isn't a totally fair statement). Michael Levitt has done a bunch of things, with no one big software package, but he was one of the earliest people trying to do ab initio protein structure prediction. He was also one of the first people to really start categorizing protein structure in a way that allowed for computational modeling -- back in the 70s and early 80s. Arieh Warshel is probably best known for bridging the gap between quantum mechanics and the (relatively quick-and-dirty) molecular mechanics work. He's done a whole bunch of work modeling enzymatic reactions, coming up with better electrostatic models, and other things where quantum mechanics does a good job, but is way too slow to be used on giant molecules like proteins.

alexholehouse 13y ago
Don't forget Karplus' colossal contribution to NMR
- dnautics 13y ago
  yeah, I'd say that is way more important to science. I have never used and never would use CHARMM, Karplus' J-coupling values - indispensable.
- timr 13y ago
  I had a whole other paragraph about that, but took it out because I figured that most people on HN wouldn't even know what NMR is, let alone NMR structure prediction. These guys have collectively done so much stuff that it's impossible to give a fair accounting of it all in a brief post.
bbgm 13y ago
Yes, but I am also not surprised given this is pretty fundamental work, even if it hasn't quite hit the sort of revolutionary goals many of us hoped for. If Peter Kollman had been alive, I suspect he would have shared this Nobel. This Nobel is hits very close to home. Much of my PhD work was done in CHARMM and I come from the Karplus lineage, and at one point in time I had pretty much read every paper Levitt and Warshel had ever written.
- varelse 13y ago
  Why no Harold Scheraga? Seriously...
  - timr 13y ago
    I thought the same thing.
- hyperbovine 13y ago
  According to press accounts, a maximum of three people can share the Nobel prize.
bbgm 13y ago
The beauty of CHARMM (at the time) was that it was the first practical combination of a forcefield and MD engine, that made it practical to simulation proteins. While other packages have left it behind on perf and capability, the forcefield itself remains very high quality, and the breadth of functionality is still as good as it gets. Unfortunately the implementation could do with an overhaul since it still looked like something from the early 80s (I haven't seen the CHARMM code in 5 years)
- davecap1 13y ago
  It's still mostly fortran :)
- Xcelerate 13y ago
  > the forcefield itself remains very high quality, and the breadth of functionality is still as good as it gets. It's kind of weird that forcefields haven't improved all that much. Implementation has improved drastically (LAMMPS, Gromacs, etc.) and QM level theory has too (FCIQMC, exploiting symmetries to eliminate the sign problem), but MD forcefields don't seem to have made a whole lot of progress from CHARMM, AMBER, and UFF. I suppose some of the reactive potentials (AIREBO and Tersoff) are a step up, but still...
  - acadien 13y ago
    Maybe that's true for biological compounds, but for the rest of the periodic table new potentials are constantly being developed (and some may even be improvements). Semiconductors, transition metals, heavy elements, ferromagnetics, you name it... its being worked on. Actually even for biological molecules there are still advances being made. Water is an excellent example seeing how there is a new potential released once every 6 months or so. Its difficult to say whether these actually show a quantifiable improvement over old potentials, but its still an area of constant effort and progress.
    - Xcelerate 13y ago
      > whether these actually show a quantifiable improvement over old potentials Yeah, that's what I was meaning with regard to force-fields in general. What are we, like TIP23P for water now? ;)
return0 13y ago
Computational methods are powerful, but not respected enough in many fields. I think it's harder to publish computational work in a respectable journal, but rather easier when it's wet lab work. I think it was a good choice of the Nobel committee that may change scientists' view of computational work.
iskander 13y ago
Since you seem to know about this field, any chance you can share you opinion on the working going at DE Shaw Research? Does developing custom hardware for molecular dynamics give them any sort of qualitative advantage? Are the systems they're simulating significantly larger or more useful than what other groups work on?
- cing 13y ago
  I know a thing or two about the field. Custom hardware for molecular dynamics allows one to simulate longer timescale biological processes, namely the folding of larger proteins. More generally, in the study of any size protein, countless molecular dynamics papers are simply plagued with statistical error and cannot be trusted. I think it's unanimous that DE Shaw Research is doing a great service and I'm excited to see the performance of their next supercomputer, Anton2, http://dl.acm.org/citation.cfm?id=2451175 http://dl.acm.org/citation.cfm?id=2451175
  - varelse 13y ago
    But as in all things, Anton makes a controversial set of assumptions and approximations w/r to long-range electrostatics so it's anyone's guess whether their approach is valid or not. All that aside, Anton is a wicked cool piece of hardware able to accelerate their approximation of traditional molecular dynamics by a factor of 50 over GPUs and up to a factor of 500 over CPU clusters, hitting milliseconds of simulated protein time in a single trajectory. And since it's the only hardware capable of simulating a single monotonic trajectory out to that timescale, it's challenging to compare it to other approaches.
    - timr 13y ago
      Agreed. DE Shaw's hardware work is very cool, but I'm in the camp that believes that the force fields suck (in general; not just theirs), and bashing through some multi-millisecond trajectories will only highlight their limitations.
      - 13y ago

by timr 13y ago

alexholehouse 13y ago

Don't forget Karplus' colossal contribution to NMR

dnautics 13y ago
yeah, I'd say that is way more important to science. I have never used and never would use CHARMM, Karplus' J-coupling values - indispensable.
timr 13y ago
I had a whole other paragraph about that, but took it out because I figured that most people on HN wouldn't even know what NMR is, let alone NMR structure prediction. These guys have collectively done so much stuff that it's impossible to give a fair accounting of it all in a brief post.

bbgm 13y ago

Yes, but I am also not surprised given this is pretty fundamental work, even if it hasn't quite hit the sort of revolutionary goals many of us hoped for. If Peter Kollman had been alive, I suspect he would have shared this Nobel. This Nobel is hits very close to home. Much of my PhD work was done in CHARMM and I come from the Karplus lineage, and at one point in time I had pretty much read every paper Levitt and Warshel had ever written.

varelse 13y ago
Why no Harold Scheraga? Seriously...
- timr 13y ago
  I thought the same thing.
hyperbovine 13y ago
According to press accounts, a maximum of three people can share the Nobel prize.

bbgm 13y ago

The beauty of CHARMM (at the time) was that it was the first practical combination of a forcefield and MD engine, that made it practical to simulation proteins. While other packages have left it behind on perf and capability, the forcefield itself remains very high quality, and the breadth of functionality is still as good as it gets. Unfortunately the implementation could do with an overhaul since it still looked like something from the early 80s (I haven't seen the CHARMM code in 5 years)

davecap1 13y ago
It's still mostly fortran :)
Xcelerate 13y ago
> the forcefield itself remains very high quality, and the breadth of functionality is still as good as it gets. It's kind of weird that forcefields haven't improved all that much. Implementation has improved drastically (LAMMPS, Gromacs, etc.) and QM level theory has too (FCIQMC, exploiting symmetries to eliminate the sign problem), but MD forcefields don't seem to have made a whole lot of progress from CHARMM, AMBER, and UFF. I suppose some of the reactive potentials (AIREBO and Tersoff) are a step up, but still...
- acadien 13y ago
  Maybe that's true for biological compounds, but for the rest of the periodic table new potentials are constantly being developed (and some may even be improvements). Semiconductors, transition metals, heavy elements, ferromagnetics, you name it... its being worked on. Actually even for biological molecules there are still advances being made. Water is an excellent example seeing how there is a new potential released once every 6 months or so. Its difficult to say whether these actually show a quantifiable improvement over old potentials, but its still an area of constant effort and progress.
  - Xcelerate 13y ago
    > whether these actually show a quantifiable improvement over old potentials Yeah, that's what I was meaning with regard to force-fields in general. What are we, like TIP23P for water now? ;)

return0 13y ago

Computational methods are powerful, but not respected enough in many fields. I think it's harder to publish computational work in a respectable journal, but rather easier when it's wet lab work. I think it was a good choice of the Nobel committee that may change scientists' view of computational work.

iskander 13y ago

Since you seem to know about this field, any chance you can share you opinion on the working going at DE Shaw Research? Does developing custom hardware for molecular dynamics give them any sort of qualitative advantage? Are the systems they're simulating significantly larger or more useful than what other groups work on?

cing 13y ago
I know a thing or two about the field. Custom hardware for molecular dynamics allows one to simulate longer timescale biological processes, namely the folding of larger proteins. More generally, in the study of any size protein, countless molecular dynamics papers are simply plagued with statistical error and cannot be trusted. I think it's unanimous that DE Shaw Research is doing a great service and I'm excited to see the performance of their next supercomputer, Anton2, http://dl.acm.org/citation.cfm?id=2451175 http://dl.acm.org/citation.cfm?id=2451175
- varelse 13y ago
  But as in all things, Anton makes a controversial set of assumptions and approximations w/r to long-range electrostatics so it's anyone's guess whether their approach is valid or not. All that aside, Anton is a wicked cool piece of hardware able to accelerate their approximation of traditional molecular dynamics by a factor of 50 over GPUs and up to a factor of 500 over CPU clusters, hitting milliseconds of simulated protein time in a single trajectory. And since it's the only hardware capable of simulating a single monotonic trajectory out to that timescale, it's challenging to compare it to other approaches.
  - timr 13y ago
    Agreed. DE Shaw's hardware work is very cool, but I'm in the camp that believes that the force fields suck (in general; not just theirs), and bashing through some multi-millisecond trajectories will only highlight their limitations.
    - 13y ago