Posts by Shawn
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Message boards :
Rosetta@home Science :
Design of protein-protein interfaces
(Message 72713)
Posted 9 Apr 2012 by Shawn Post: Those of you who followed this thread from the beginning might be aware of efforts of Sarel and Tim, as well as others in the lab, to design binders to influenza virus hemagglutinin. That project has been very successful, as Rosetta@home contributors helped identify two proteins (HB36 and HB80) that bound to group 1 influenza A subtypes (such as H1 and H5) with very high affinity. For the more technically inclined, you can read about this development here: http://www.sciencemag.org/content/332/6031/816.full Given the success of this project, more scientists in the lab are now working on designing new binders to bind other influenza subtypes, such as H3. In the long term, we would like to develop a variety of antibodies that bind to different combinations of influenza subtypes with different specificities, which could offer potentially interesting therapeutic and diagnostic applications. You will be seeing (and may have already seen) jobs with descriptions such as "H3 Influenza Binder". Hopefully, that helps clarify what you are volunteering your computational resources towards! Thank you so much for your time, not only with your computers, but also providing us valuable feedback on these forums! |
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Message boards :
Number crunching :
MiniRosetta 3.17 Problems.
(Message 71516)
Posted 27 Oct 2011 by Shawn Post: Thanks for letting us know. I think we've identified the problem, and the ProteinInterfaceDesign team is now aware of the issue. Thanks once again for your time, your computational resources, and your feedback! |
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Message boards :
Number crunching :
MiniRosetta 3.17 Problems.
(Message 71513)
Posted 27 Oct 2011 by Shawn Post: Thanks for letting us know. As you are probably aware, we recently changed our version of Rosetta@home. These current jobs are associated with protocols written for an older version. I did not notice any compatibility problems at the time, but I will do some more testing on these jobs to find out why they didn't work. |
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4)
Message boards :
Number crunching :
Problems and Technical Issues with Rosetta@home
(Message 70469)
Posted 31 May 2011 by Shawn Post: I spoke to dekim about the crediting issue, and he believes it's related to the fact that there were no work units sent out last week. Since we have plenty of work queued up now, this shouldn't be an issue, but if it persists this week, please let me know again. |
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5)
Message boards :
Number crunching :
Problems and Technical Issues with Rosetta@home
(Message 70453)
Posted 30 May 2011 by Shawn Post: Hey guys, I'm not too familiar with how credits are awarded, but I'll answer to the best of my knowledge. As I have previously mentioned, my protocol is a pretty "jumpy" one, in which some trajectories take much longer than others. In fact, the ones that tend to be short are the ones that finish at the very beginning, because the protocol has identified those guys as being "non-productive". So basically, at the very beginning, you will have generated a bunch of models really quickly. However, if you have a model that's running more slowly, unfortunately, you might not earn as much credit, but on the other hand, those runs are much more likely to provide a useful structure, so the time you spend on those longer models is very much appreciated! However, the credit assigned for these protocols is normalized to a running-average of how long each work unit takes. Since this number is constantly changing, and because the distribution of "long vs. short" jobs is skewed, I'm not surprised that the credits awarded is a little bit finicky. But crunching more models isn't causing your credits to go down; it would have gone down anyway (and to a greater extent) because of the peculiarities of the normalization. I'll check sometime this week with other lab members who are more familiar with this process when they are available though. |
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6)
Message boards :
Number crunching :
Problems and Technical Issues with Rosetta@home
(Message 70425)
Posted 28 May 2011 by Shawn Post: Hey guys, I submitted a new job for MVH, which you can read about in the protein-protein interface thread if you're interested. This job is slightly different from the previous ones (it includes more stubs), so I wanted to do some extra checking to make sure that it wouldn't break anything. Hopefully, I'll get some jobs for Ebola targets later this week! |
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7)
Message boards :
Rosetta@home Science :
Design of protein-protein interfaces
(Message 70386)
Posted 23 May 2011 by Shawn Post: I promised an update on my Ebola project, and I've recently focused more of my time on this target, so I thought I'd give you guys another update! As you might know, Ebola virus causes terrible hemorrhagic fever, which usually results in death in the patient 6-9 days after the onset of symptoms. Unfortunately, there are currently no therapeutics available for human use, but hopefully, we can do something to change that. Recently, researchers at the Scripps Institute were able to determine the crystal structure of the Ebola virus surface glycoprotein (GP) in conjunction with a neutralizing antibody (KZ52) from a human survivor of a 1995 outbreak in the former Zaire. KZ52 interacts with both the GP1 and GP2 subunits of the GP complex, but more so with GP2. We're trying to use the hotspot method (which I mentioned during my discussion of the measles project) to design our protein, which would bind GP in roughly the same place that KZ52 also binds. A very preliminary picture of some of stubs we're considering looks as follows:  Of course, computational design of protein binders is tricky, and each specific project also has its own particular challenges. In this case, there isn't much surface area for KZ52 to interact with GP, but we're hoping to design a binder that can make more use of the surface that is available. Thanks once again for being involved with Rosetta@home! I'm really excited about this project, and I would love to share it with everyone, so once again, please let me know if you have any questions or comments! |
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8)
Message boards :
Rosetta@home Science :
Design of protein-protein interfaces
(Message 70367)
Posted 17 May 2011 by Shawn Post: I wanted to address some of the issues posted recently by Rosetta@home users in this thread, as they pertained specifically to protein interface design. As you might be aware, these types of jobs (including my MVH ones) tend to be a bit "jumpy" in terms of how long the trajectories take. Sometimes, one hour of CPU time might yield a lot of structures (and 100 credits). Other times, a trajectory on one model might take a long time, and nearly 6 hours of CPU time might yield less than 3 credits, as unfortunately happened to Warped. The amount of credit granted is normalized for each job type, so hopefully next time you are assigned one of these jobs, you'll be lucky enough to get more credits. If you are assigned one of the longer tasks (and we have no way of knowing beforehand which tasks are longer), you unfortunately won't get as many credits. But on the other hand, these longer trajectories tend to result in better design models--if you're naturally optimistic, you might be happy that you've stumbled into one of the tasks that are more likely yield an MVH inhibitor! =) In the meantime, I will be submitting new MVH jobs but managing the workunits so that don't take as long to compute and are less "jumpy" in terms of overall length. Sarel has also developed new options for our protocols that would also help in this regard, and David K and other members of the lab are working hard to get those features integrated into Rosetta@home. Thanks again for your contributions! |
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9)
Message boards :
Rosetta@home Science :
Design of protein-protein interfaces
(Message 70361)
Posted 17 May 2011 by Shawn Post: Hey guys, thanks for the feedback on the MVH jobs. I'll see what I can do to keep the tasks more manageable. |
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10)
Message boards :
Rosetta@home Science :
Design of protein-protein interfaces
(Message 70331)
Posted 13 May 2011 by Shawn Post: I am running a couple of these tasks and need to reboot my computer and do not want to lose hours of core time when there is some way of avoiding this. I cannot sit for ages checking on the task properties. Also, have you been having problems with one particular set of jobs, or is it a more general problem with many different Rosetta@home jobs? |
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11)
Message boards :
Rosetta@home Science :
Design of protein-protein interfaces
(Message 70330)
Posted 13 May 2011 by Shawn Post: I am running a couple of these tasks and need to reboot my computer and do not want to lose hours of core time when there is some way of avoiding this. I cannot sit for ages checking on the task properties. Thanks for the feedback, we're looking into this! |
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12)
Message boards :
Rosetta@home Science :
Design of protein-protein interfaces
(Message 70296)
Posted 9 May 2011 by Shawn Post: What will your tasks be called so we know when they come to our systems? Hi! Hey, this is correct! I'll be submitting a lot of different jobs for these guys with different strategies, but all of them will begin with "MVH_" and will contain "ProteinInterfaceDesign" in the middle! |
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13)
Message boards :
Rosetta@home Science :
Design of protein-protein interfaces
(Message 70240)
Posted 4 May 2011 by Shawn Post: As I had alluded to earlier, I am working on a protein to bind to the hemagglutinin protein (MV-H) of measles virus. Measles is a significant cause of childhood morbidity and mortality worldwide. Measles virus enters our cells in a two-step process: an attachment protein allows it to bind to a host cell receptor, which allows a second protein to mediate fusion of the virus to the host cell. MV-H is the attachment protein responsible for the first step, and SLAM (or CD150) is the predominant host cell receptor to which MV-H binds. Recently, researchers were able to solve crystal structures of MV-H in complex with SLAM. As you might imagine, a high-resolution structure of the target (MV-H) is crucial to our design efforts, so we were quite excited about this development! In several recent design efforts in the Baker lab, such as with influenza, we identified several "hotspot" residues on the target surface; although these hotspots made up only a small portion of the surface, they contributed a very large proportion to the binding interaction. We designed disembodied amino acid residues ("stubs") to interact specifically in these regions and then fit the rest of the designed protein accordingly around these stubs. Likewise, in our measles project, we have identified hotspots on MV-H where we would like our protein to bind. One interesting challenge unique to measles is that our hotspot approach focuses on charged amino acids such as lysines to bind to oppositely charged regions of MV-H. Most of the previous success we have had involved binding to hydrophobic regions, but we'd like to push the envelope on what we can do!  I think the final designed protein binder will include some subset of the amino acids depicted above. It would bind MV-H where it would have bound to SLAM, thereby preventing its entry into our cells. However, in order to find a possibly successful design, we have to search through an astronomically large number of configurations, and the assistance of Rosetta@home users is of critical importance to this effort. So once again, thank you very much for your contributions to our research! Please let me know if you have any questions or comments! |
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14)
Message boards :
Number crunching :
Validate Errors
(Message 70172)
Posted 30 Apr 2011 by Shawn Post: What is up with these WUs? This looks like a job that was canceled while your computer was in the process of running it, which explains why you're getting those errors. However, credit was granted anyway. |
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15)
Message boards :
Number crunching :
Problems and Technical Issues with Rosetta@home
(Message 70170)
Posted 29 Apr 2011 by Shawn Post: Thank you for helping to deal with these. This morning I have seen a number of errors with a different signature. These run for 3-5 minutes before producing an error and exiting. The characteristic error seems to be: Hey Hank, thanks for letting us know. This job has been deleted and is no longer on the queue. Apparently, this was a small test job that reported failure early, and the author marked them for deletion right away, but sometimes those jobs propagate for a while anyway. In any case, you shouldn't see this particular job anymore, but if for some reason it persists, please give us an update! |
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16)
Message boards :
Number crunching :
Problems and Technical Issues with Rosetta@home
(Message 70158)
Posted 28 Apr 2011 by Shawn Post: We are aware that we have had some issues with bad jobs on Rosetta@home recently. We try to ensure that these bad jobs don't slip through, but they occasionally do. When that happens, your efforts to alert us to these problems are extremely important and very much appreciated. In order to ensure that we address technical issues promptly, graduate students in the Baker lab (such as myself) will be regularly monitoring this message board for such problems. This will be in addition to the help of Mod.Sense, our vigilant forum moderator who has done a lot to ensure that these projects run as smoothly as possible. I ask that you alert us to new issues in this thread so that we can find them more easily. Thank you all once again for your commitment to Rosetta@home! |
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17)
Message boards :
Rosetta@home Science :
Design of protein-protein interfaces
(Message 70152)
Posted 28 Apr 2011 by Shawn Post: Hello, My name is Shawn Yu, and I'm a new graduate student in the Baker lab. I have several really exciting projects in protein-protein interface design that I want to share with everyone involved with Rosetta@home. I'm designing proteins to bind to targets on the measles and Ebola viruses. De novo protein-protein interface design has been an elusive problem in the field for quite some time. It is an extremely challenging endeavor that will require us to continually refine our algorithms and seek more computional power. Relatively recently--due in large part to the generosity and support of Rosetta@home users--we able to tackle these problems with reasonable expectation of success, as demonstrated with the influenza project, but we would like to continue to expand on this success. Each viral target represents a different challenge that tests our knowledge of how protein interacts in different ways, so they are really interesting for their scientific merits alone. Furthermore, these methods are mutually reinforcing, so with more successful designs we'll have a better idea of what works and what doesn't work. In the long term, I hope the results from these projects can form the basis of future protein-based therapies, and I know many Rosetta@home users like myself contribute their time because they hope to help find cures to these diseases. Over the next week, I will be discussing more details about my projects. In the meantime, thank you so much for volunteering your time and your computers to help to our projects. You are making a major contribution to our research! -- Shawn |
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