Ratika,

Updates are always exceedingly welcome, as I enjoy perusing the fruits of my (but mostly other people's) labor.

Would it be possible to release some kind of weekly or monthly email containing all the updates posted in that period of time? I could subscribe to this forum thread, but admittedly fora are places for multi-directional conversation, and at times I just want to hear from one speaker.

In more vaccine-related news –
Researchers at the Institute for Protein Design and collaborators have invented a new method to design novel proteins to be used as a candidate vaccine against respiratory syncytial virus (RSV).
These studies are detailed in a recent Nature paper (February 2014) entitled Proof of Principle for Epitope-Focused Vaccine Design.

RSV causes infection of the lungs and breathing passages, and is a significant cause of infant mortality. In addition to other viruses, including HIV, RSV has resisted traditional vaccine development. To address this, a new computational Rosetta program (Fold From Loops) was developed to design flexible protein scaffolds around a functional fragment of interest – in this case a known neutralizing epitope from RSV. These designed protein scaffolds accurately mimicked the viral epitope structure. The candidate vaccines were injected into rhesus macaques and this immunization resulted in the production of virus neutralizing antibodies.

This successful proof of concept for epitope-focused vaccine design highlights the potential for this protein design method to generate vaccines for RSV, HIV and other pathogens that have to-date been difficult to stop.

There are some great articles written on this research that go into further detail. Please check them out:

Science 2.0 has an article on this important breakthrough in application of computational protein design to vaccines.
http://www.science20.com/catarina_amorim/major_breakthrough_vaccine_design-129214

The Scripps Research Institute also has a nice press release on this work.
https://www.scripps.edu/news/press/2014/20140205schief.html

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:

Hi, Tom

W've tested Fold-I twice: before and after the release date, 06/30/2009.
One is in 2008, and the other is 03/10/2011.
This is because the rosetta parameters was changed, so we tested it again.

best.
Nobuyasu Koga

Hi, Tom

Date for computationally created and tested on Rosetta@HOME are

Fold-I : 03/10/2011
Fold-II : 01/30/2012
Fold-III: 06/13/2011
Fold-IV: 10/17/2011
Fold-V : 08/14/2011

Date for experimentally determined by NMR:

Fold-I : 06/30/2009
Fold-II : 06/29/2012
Fold-III: 12/15/2011
Fold-IV: 06/30/2012
Fold-V : 05/15/2012

Actually, the energy landscape of Fold-I were resampled after when we experimentally determined the structure, because the Rosetta potential functions were changed. That's why the tested date on Rosetta@HOME is after the experimentally determined date.
As I remember, the first time when we tested for Fold-I was probably 2008. But I don't have a exact record for that time. Sorry.

Currently, we're designing bigger proteins of which residues are more than > 100 !
This is a certainly big step for us. You know our designed proteins were less than 100.
How big proteins we can design ? Can we apply the same rules for designing bigger proteins ?
I hope I can update great news soon !

thanks !

Hi, Tom

Date for computationally created and tested on Rosetta@HOME are

Fold-I : 03/10/2011
Fold-II : 01/30/2012
Fold-III: 06/13/2011
Fold-IV: 10/17/2011
Fold-V : 08/14/2011

Date for experimentally determined by NMR:

Fold-I : 06/30/2009
Fold-II : 06/29/2012
Fold-III: 12/15/2011
Fold-IV: 06/30/2012
Fold-V : 05/15/2012

Actually, the energy landscape of Fold-I were resampled after when we experimentally determined the structure, because the Rosetta potential functions were changed. That's why the tested date on Rosetta@HOME is after the experimentally determined date.
As I remember, the first time when we tested for Fold-I was probably 2008. But I don't have a exact record for that time. Sorry.

Currently, we're designing bigger proteins of which residues are more than > 100 !
This is a certainly big step for us. You know our designed proteins were less than 100.
How big proteins we can design ? Can we apply the same rules for designing bigger proteins ?
I hope I can update great news soon !

thanks !

Thanks for the reply !!

It should be able to design protein binders to viruses or cancer related proteins for cure. I'm not expert on the autoimmune disorder, but it is highly possible to design novel medicine to inhibit/block the antibody that induce autoimmune disorder.

With your help, we have made an exciting breakthrough in protein design that is reported in a research article titled "Principles for designing ideal protein structures" in the journal Nature today. You can read about it at

http://www.nature.com/news/proteins-made-to-order-1.11767

In this paper, we describe general principles for creating new proteins from scratch. The new Institute for Protein Design is using these principles to design new proteins to treat disease.

Rosetta@home was absolutely critical to this work as described in the news article; Figure 3 in the paper shows how all of your contributions were used to test designed sequences to see if they folded up to the right structure. Most of the work units we are sending out on Rosetta@home these days are for exactly these kind of tests on the new proteins we are designing--this is absolutely critical to the research and to the development of new therapeutic and other functions. Thank you again for all of your contributions!

I'm happy to hear that Roseeta@Home is making progress. It's an honor to crunch for you ;)