Good call. Work units involving the design of proteins to bind to Mdm4 will contain the word "Mdm4" in their name.

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As promised, here is the continuation of the story begun in message 72155:

Project 2:
The second of these interactions involve a protein called EED and another called Ezh2. If you think about DNA as a ladder, then each of our cells has about six billion rungs worth of ladder. In order to keep all of that DNA from getting hopelessly tangled, our cells keep it on little spools, called histones, when not in use. Think of this like a massive film archive. It turns out that there is a lot of DNA that never gets used, so the cells put special flags on those spools (histones) that say something like "never use this section of DNA". EED is a large protein that attaches to those flags and brings along Ezh2, a "flagging machine" for the ride. EED makes sure that Ezh2 adds flags to histones that are supposed to get them, and not to histones carrying DNA the cell actually wants to use. Some cancer cells reduce the amounts of EED or Ezh2 to prevent flagging of DNA regions that they want to use to take over our bodies. Other cancer cells expand the amounts of EED or Ezh2 to flag DNA regions that are getting in the way. Scientists are working hard to better understand how EED, Ezh2, and friends work in normal cells and what goes wrong in cancer cells. Some are trying to develop drugs that prevent Ezh2 from attaching to EED. This means that the drugs have to stick to EED more tightly than Ezh2. Although Ezh2 attaches relatively loosely to a large patch on the surface of EED, their aren't any drugs yet available that do what we want.

I'm trying to make proteins that will do the same job. I used Rosetta@home to design a set of proteins that mimic Ezh2 in order to block it from attaching to EED. Just to give you a sense of how much computing I need for a project like this, I submitted just under two million work units to Rosetta@home, and donor's computers ran my protocol just under a billion times to give me about 54 designs to look at, from which fourteen were suitable for testing. This took about a month to run on Rosetta@home. From initial experiments, it looks like eight of the designs stick to EED, and one in particular sticks three times better than the Ezh2 found in our cells. Now I'm working to improve the best design at the lab bench and hope to send it to co-workers for testing in living cells. There's still a lot of work to be done to make sure that everything is working right with this design, but I want to give a big thank-you to all of you who donated your computer time to make this possible! For more information about EED, Ezh2, and related proteins, please visit:







Work units for this project carried the word "EED" in their name. I'll post more about the third project shortly.

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Great to hear from you!

When only I get some free time, I'll make some translations & news basing on your posts. I am pretty sure MadMax and others will be happy as well.

Kind regards from BOINC@Poland,
a.m.

And here is the third of the projects I mentioned in posts 72162 and 72155:

Project 3:
The third of these interactions involve a protein called RhoA and another protein called Dbs. Most of the cells in our bodies have the ability to crawl around on command. This is really important when we develop as embryos. Cells are crawling everywhere to get into the right spot and morph us from something that looks like an alien into something that looks like a baby. As adults, must of our cells have stopped crawling around and settled down to do their respective jobs. If you have ever cut yourself and noticed that the cut got smaller and smaller as it healed, that's because the skin cells on the edges of the cut crawled into the gap to seal it up. Cells have rigid skeletons to give them shape and keep their insides organized, so in order the crawl around, they have to constantly rearrange their skeletons as they go. Just imagine the information processing and communication that has to happen inside the cell for this to happen in an organized manner. Imagine a circus tent with a thousand people inside it and they all decide to move the tent a mile away without taking it down or anyone leaving the tent. There are lots of protein-protein interactions required for this to work right in our cells. One of these is a protein switch called RhoA. RhoA can be either in the "on" position or the "off" position. When a cell wants to crawl around, it uses Dbs to switch RhoA to the "on" position so that the cell's skeleton will be rearranged faster. When cells don't want to move around, they use proteins called RhoGAPs to turn RhoA "off" so that the cell's skeleton is rearranged more slowly. Since cancer cells grow like crazy, eventually things become crowded where they live and so some of the cancer cells decide to strike out on their own, colonizing new parts of our bodies. Doctors call this "metastasis" and it's bad news for cancer patients. In order to start crawling to a new home, a cancer cell speeds up rearrangement of the it's skeleton, either by expanding the amounts of RhoA or Dbs in the cell or by reducing the amounts of RhoGAPs so that they aren't around to turn off RhoA. RhoA is a very flexible protein and no one has been able to develop a drug that will keep RhoA turned "off" by preventing Dbs from attaching and switching it "on".

I'm trying to make proteins that will attach to RhoA and prevent Dbs from switching it "on". This is a tricky venture, since RhoA is very, very flexible and attaches only loosely to Dbs. I used Rosetta@home to design a set of 16 proteins to do the job, but none of these stuck to RhoA when tested. In the coming months I'll use Rosetta@home to try a different design strategy that I think will work. If successful, these proteins would be the first RhoA inhibitors available and should provide scientists a new tool to better study how RhoA works and how cancer cells take control of it. Work units for this project will contain the word "RhoA" in their name.

Thanks again for all of your donated computer time. You're help makes these projects possible!

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Moody:

You said "Thanks again for all of your donated computer time. You're help makes these projects possible!"

I want to say "Thank you for all your work. You're a reason why this project is worthwhile!"

Mark

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Very interesting! If only I knew this sooner :D

I do have a question, are these projects the ones that dr Baker mentions in his journal?

I also want to describe a new research direction we are now embarking on aimed at future cancer therapies. There are a small set of proteins which are frequently found at much higher levels than normal on the surface of cancer cells. We are starting to design small proteins which bind tightly to these tumor cell markers. If we are successful, we have collaborators who will be testing these proteins for their ability to target cancer cell killing agents to the tumors.

The projects that James is working on that he has described below all involve targeting proteins that are on the inside of the cell. the projects we are just beginning target proteins on the outside of cancer cells. since the rosetta@home methods allow in principle the design of tighly binding proteins to any target, we have a lot to do!

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moody
Many thanks for the information and update on current work and goals of the project!

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!

Computationally-designed Wnt Surrogate Protein

Wnt protein is widely recognized as a crucial component of vertebrate development. For more than three decades, scientists have sought to understand the structure of this important molecule. Unfortunately, obtaining a detailed understanding of Wnt's structure has proven to be quite difficult. After much work, a research group led by Dr. K. Christopher Garcia at Stanford University published the structure of Wnt bound to its target protein in June 2012. This binding event is partially facilitated by a fatty acid, an addendum to Wnt that is known to complicate molecular structure determination.
Wnt protein is secreted into the space around growing cells. It then binds to its target (Frizzled protein) on the surface of some of these cells. The attachment of Wnt to Frizzled leads to the transmission of a signal into the cell, which alters the development and physiological behavior of that cell by changing the way that the cell accesses the information in its DNA. This signaling event is modified by a number of supplementary proteins in the same pathway.
Our current project aims to replace naturally occurring Wnt with a surrogate protein through protein engineering methods. We first look at the structure of Wnt's target protein and use computer models that rely on the Baker Lab's Rosetta computational design technology to determine chemically favorable binding locations. We then look at how we might combine the mixture of possible binding sites into an optimal binding pattern. Finally, we use the distributed computing abilities of the BOINC network to attempt to find a previously-studied protein that can be seeded with our binding pattern. In a successfully engineered project, the newly created protein will show its ability to bind to the target (Frizzled in this case) during validation tests.
In parallel with our standard techniques, which already rely heavily on the CPU time of our Rosetta@home participants, we have submitted the structure of the target and a potential binder to FoldIt players. FoldIt will allow people to interact directly with the Rosetta scoring algorithms, allowing the binding region to be custom-designed with the help of real-time feedback.
The creation of a successful Wnt-surrogate binder will signify an important advance in our ability to quickly employ emerging scientific data to facilitate the clinically-focused goals of our team of molecular engineers. Binding to Frizzled should allow us to interrupt the Wnt signaling pathway in a way that will be immediately useful as a tool for the many laboratories that are focused on human development. Looking farther into the future, control of the Wnt signaling pathway may allow us to limit the growth of Wnt-mediated tumors and may even prove useful in tissue engineering. Through the efforts of the scientists in the Baker Lab, our partners who dedicate their computing time to Rosetta@home, and FoldIt players, we will begin testing the preliminary designs for a Wnt surrogate at our principal laboratory in Seattle, Washington in late August 2012.

Thanks for the update!

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Thanks for the new information. Always interested to hear what my workunits might be contributing to.

Thanks for new information from Science part!

Hi.
Last days i see in queue lof of WUs from protein-protein interfaces series with names like
Ebolanator3_..._ProteinInterfaceDesign_2Sep2012...
It new research target?
Probably connected to Ebola virus? Or it just similar name?

Yes! we are now trying to design drugs that prevent Ebola from killing people-with your help hopefully we will succeed!

Hi.
Last days i see in queue lof of WUs from protein-protein interfaces series with names like
Ebolanator3_..._ProteinInterfaceDesign_2Sep2012...
It new research target?
Probably connected to Ebola virus? Or it just similar name?

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In response to recent requests for an update on what we are doing with your donated computer time, here goes:

Project 1:
The first of these interactions involves a protein called p53 and another called Mdm4. Thanks for lending us your spare computer time. Projects like this one require so much computational time that they would be impossible without you. I'll post more about the other two projects at a later date.

Any news about this project??

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To all of our wonderful Rosetta@Home contributors,

Here is an update about the p53-Mdm4 project: Using Rosetta@Home, we identified a set of 14 proteins that could be modified to stick to Mdm4 while ignoring Mdm4. We synthesized these proteins, tested them, and identified one that sticks to Mdm4 about 75 times better than it sticks to Mdm2. We sent this protein, called Mdm4 Binder 17 (MB17) to St. Jude's Childrens Research Hospital so the cancer experts could test it in cancer cells. So far, they have confirmed that MB17 strongly prefers to stick to Mdm4 over Mdm2 (about 170 times better, in their experiments). They also found that MB17 works correctly inside living cells, a major milestone for a designed protein. In the mean time, we've created new versions of MB17 that preference Mdm4 even more (about 370 times more than Mdm2), some that pinch-hit and prefer Mdm2 instead of Mdm4 (about 120 times more than Mdm4), and some that like both Mdm4 and Mdm2 equally well. The folks at St. Judes are starting to work with these improved variants as well. This is the first time that the cancer research community has ever had a tool to knock out just Mdm4 while leaving Mdm2 alone, so naturally, the folks at St. Jude's are pretty excited. They are gearing up to test MB17 in real cancer cells so we'll keep our fingers crossed. We'll keep you updated as new developments arise. I'm sorry for the long delays between posts. Things are pretty busy around here. For those of you seeing this thread for the first time, I've re-posted below what I posted previously about this topic:

Project 1:
The first of these interactions involves a protein called p53 and another called Mdm4. p53 is a communication hub in our cells, used to translate information about unwanted DNA mutations into an effective response by the cell. The activity of p53 is modulated by a pair of other proteins, Mdm4 and Mdm2, which act to shut off p53 when all is well. Cancer cells depend on DNA mutations to stay alive and so they find ways to shut off p53, either by reducing the amount available p53 or by expanding the amount of available Mdm4 or Mdm2. that way p53 doesn't rat out mutations that the cancer might need to survive. Scientists have spent a lot of time trying to understand how Mdm4 and Mdm2 work. They do this by shutting off Mdm2 and Mdm4 with drugs. There are even drugs that will shut off just Mdm2. There are no drugs, however, that will shut off just Mdm4. So I'm trying to make one. This is a tricky process since Mdm2 and Mdm4 are very similar, making it hard for proteins to tell them apart.

I aim to use Rosetta@home to design proteins that will attach to Mdm4 while ignoring Mdm2. I hope to provide a research tool to scientists that work on Mdm4, Mdm2 and p53, allowing them to better understand how this critical communication hub works. I hope that this leads to new cancer treatments. So far, I've used Rosetta@home to design 26 proteins that should attach to Mdm4 but not Mdm2. Many of the designed proteins do stick to Mdm4, but unfortunately, they also stick to Mdm2. I am working on a third round of design using a new approach that I hope will work. For more info about the proteins involved in this project, please visit the links below:

To all of our wonderful Rosetta@Home contributors,

Here is an update about the p53-Mdm4 project: Using Rosetta@Home, we identified a set of 14 proteins that could be modified to stick to Mdm4 while ignoring Mdm4.

Thats' great!!!!

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Moody:

Thanks VERY much for the update. Rosetta is the only BOINC project for which I look at the "Science" message board before turning to the "Number Crunching" board. I do so because of posts such as your post. It is truly fascinating to read about the science being explored and created!

Thanks again.

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2 moody
Thanks for science update!