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IPDtechwriter
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Message 76455 - Posted: 19 Feb 2014, 22:53:22 UTC
Last modified: 19 Feb 2014, 22:55:34 UTC

Hi R@h users! My name is Ratika and I am a scientific and technical writer at the Institute for Protein Design (http://depts.washington.edu/ipd/) and the Baker lab (http://depts.washington.edu/bakerpg/drupal/).

As David Baker has stated before, all of you Rosetta@home volunteers have made invaluable contributions to our research projects. To keep the community up to speed as new research is published, I will be regularly updating this thread with information on recent publications and a short description of the work.

I will also try to update any project-specific threads that currently exist.

Thank you all for helping us with our project!
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Message 76456 - Posted: 19 Feb 2014, 23:06:15 UTC
Last modified: 19 Feb 2014, 23:11:19 UTC

Computational Design of an Enzyme-Based Protein Inhibitor

Computational design of protein-protein interactions to generate new binding proteins for any specified site or surface of interest on a target protein can lead to a number of novel therapeutic and biochemical tools. In recent work, novel proteins have been designed to bind to a conserved epitope on influenza hemagglutinin.

Computational design of a protein that binds polar surfaces, however, has not been previously accomplished. In a paper published in the Journal of Molecular Biology, Procko et al describe the computational design of a protein-based enzyme inhibitor that binds the polar active site of hen egg lysosome (HEL). A hot spot design approach first identified key, conserved interaction residues that contribute to much of the binding energy to HEL within a large interface. Rosetta software then identified a protein scaffold that supported the hot spots while also optimizing contact with surrounding surfaces to obtain a high affinity protein binder.

Click here to read more about this work: http://depts.washington.edu/bakerpg/drupal/Computational-design-of-a-protein-based-enzyme-inhibitor-pub
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Message 76464 - Posted: 20 Feb 2014, 14:57:20 UTC

Nice to hear you will be posting frequently Ratika. You\'ve said a mouthful here:
...novel proteins have been designed to bind to a conserved epitope on influenza hemagglutinin


Could you define what that really means to a layperson? I know a \"novel\" protein is one that basically was invented or designed; it was not found in nature. But what is a \"conserved epitope\" and what is achieved when a protein binds to one in a influenza hemagglutinin?
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Message 76488 - Posted: 24 Feb 2014, 0:45:56 UTC - in response to Message 76464.  

Could you define what that really means to a layperson? I know a \"novel\" protein is one that basically was invented or designed; it was not found in nature. But what is a \"conserved epitope\" and what is achieved when a protein binds to one in a influenza hemagglutinin?


Absolutely. I’ll be sure to explain in better detail in future posts.
Yes, as you stated, novel proteins are those that don’t already exist in nature – they are invented or designed. In the influenza example I mentioned, a novel protein was designed to bind to a conserved epitope of the flu virus protein hemagglutinin (HA). The epitope is the region of a protein where an antibody binds. On HA, this particular epitope region is the same for all the related subtypes of influenza and even when the virus mutates, the region stays the same (conserved). Binding of the designed protein to this particular site inhibits conformational changes in HA that usually drives flu virus replication. These studies highlight the potential for computational design of antiviral proteins.
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Message 76489 - Posted: 24 Feb 2014, 2:57:30 UTC

So... once further tested and studied, the potential is that one flu shot prevents any year\'s flu strains from replicating in your body. No need for a shot a year with multiple new strains in each. No fear of pandemic from influenza (once the majority have been immunized).

I guess I may be overreaching it there. Because you didn\'t say this is an immunization. But at least it would mean that when you go to the doctor and they say you have the flu, they\'d have a ready cure available. Which would also mean that the doctor doesn\'t have to just say \"it\'s a virus, it must run it\'s course\". And when similar inhibitors are found for other viruses, then medical science will have tools to treat a variety of viral infections.

Of particular note is the HIV virus. It mutates a lot, but there are \"conserved\" areas of it as well. Devising a binding protein doesn\'t necessarily mean the virus won\'t be able to replicate, but it changes the shape and generally is disruptive to the function of what it is bound to.
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Message 76497 - Posted: 27 Feb 2014, 18:55:38 UTC

Here is an article from the Protein Data Bank - February 2014 Molecule of the Month by David Goodsell - about broadly neutralizing antibodies and vaccine design

http://www.rcsb.org/pdb/101/motm.do?momID=170
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Message 76499 - Posted: 27 Feb 2014, 21:26:21 UTC
Last modified: 27 Feb 2014, 21:27:12 UTC

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
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Message 76510 - Posted: 9 Mar 2014, 6:08:42 UTC - in response to Message 76499.  

Great thread, thanks for taking the time to keep the community updated on the work that comes out of this project!
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Message 76537 - Posted: 21 Mar 2014, 18:30:54 UTC

Here is a short review on the First Computationally Designed Metalloprotein Using an Unnatural Amino Acid

Proteins that require a metal ion cofactor, metalloproteins, make up close to half of all naturally existing proteins. Metalloproteins range in function from facilitating storage and transport processes in the cell to catalyzing nitrogen fixation and molecular oxygen reduction to mediating signal transduction. Given their prevalence, functional design of novel metalloproteins will both provide a better understanding of how they work and result in the development of protein tools that have therapeutic, biotechnological, and environmental applications. What if scientists could design proteins to capture specific metals from our environment? The utility for cleaning up metals from waste water, soils, and our bodies could be tremendous.

Dr. Jeremy Mills and collaborators in Dr. Baker’s group address this challenge in the first reported use of computational protein design software, Rosetta, to engineer a new metal binding protein (“MB-07”) which incorporates an “unnatural amino acid” (UAA) to achieve very high affinity binding to metal cations. This work, Computational design of an unnatural amino acid dependent metalloprotein with atomic level accuracy, is published in the Journal of American Chemical Society.

Some background on UAAs:

With few exceptions, naturally occurring proteins are constructed from only 20 amino acids. However, recent technological advances have afforded researchers the ability to genetically encode amino acids that do not exist in nature, UAAs, into naturally occurring proteins. The UAAs are used to enhance, alter, or study protein functions. For example, UAA side chains can be incorporated into proteins to serve as orthogonal reactive groups to include elements such as fluorescent probes, DNA conjugates, and a host of posttranslational modifications — a characteristic otherwise not afforded by the canonical 20 amino acids.

The UAA used by Mills et al is (2,2′-bipyridin-5yl)alanine, or “Bpy-Ala” which has the ability to bind a variety of di-valent metal cations. The remainder of the computationally defined metal binding site is constructed from the 20 native protein side chains. This binding site, in addition to the UAA, greatly increases the metal binding affinity of the designed protein.

This new metalloprotein has been shown to tightly bind many biologically relevant metal ions including zinc, iron, nickel, and cobalt, as well as some metals that occur less often in nature like palladium. A designed metalloprotein such as MB_07 may have a strong environmental impact as an integral reagent in removing toxic and radioactive materials from wastewater streams. This metal-scavenging activity could also be advantageously employed in cases such as blood detoxification by efficiently titrating out and sequestering the toxic culprit. Furthermore, the design of metalloproteins with new catalytic activities (metalloenzymes) would facilitate the exploration of more efficient, cost-effective, and environmentally friendly alternatives to catalysts currently used in many synthetic and industrial chemical reactions.

To read this review on the IPD website and to see a crystal structure of MB_07 please follow this link:

http://depts.washington.edu/ipd/first-computationally-designed-metalloprotein-using-an-unnatural-amino-acid/
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Message 76574 - Posted: 31 Mar 2014, 22:54:45 UTC

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.
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Message 76580 - Posted: 2 Apr 2014, 13:26:23 UTC - in response to Message 76499.  

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


Tom wrote the below:

Is the program Rosetta program (Fold From Loops)used by Rosetta members of the community in Rosetta@home Did the Rosetta community help with the vaccines development in your article. Thanks, Tom
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Message 76581 - Posted: 2 Apr 2014, 13:28:58 UTC - in response to Message 76574.  

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.


Tom

This sounds good for me to have a monthly or weekly newsletter.

Thanks,
Tom
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Message 76582 - Posted: 2 Apr 2014, 19:10:36 UTC

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.


Any updates if the MB17 worked on the cancer cells? I can not seem to get an answer to this?

Tom Zolotor
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Message 76622 - Posted: 15 Apr 2014, 6:13:51 UTC - in response to Message 76582.  

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.


Any updates if the MB17 worked on the cancer cells? I can not seem to get an answer to this?

Tom Zolotor



experiments are still underway in our collaborators lab at St. Judes hospital
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Message 76665 - Posted: 28 Apr 2014, 17:37:41 UTC

Hi all,
We are still discussing putting together a monthly newsletter for Rosetta@home research updates. In the meantime, I will continue to post some updates here.

V-type nerve agents are among the most toxic compounds known, and are chemically related to pesticides widespread in the environment. These compounds are relatively easy to synthesize and their use by terrorist groups is a serious threat. Using an integrated approach, described in an ACS Chemical Biology paper entitled \'Engineering V-type nerve agents detoxifying enzymes using computationally focused libraries\', Dr. Izhack Cherny, Dr. Per Greisen, and collaborators increased the rate of nerve agent detoxification by the enzyme phosphotriesterase (PTE) by 5000-fold by redesigning the active site.

Computational models of PTE complexed with V-agents were constructed and Rosetta was used to design multiple rounds of libraries with active site sequence variation to improve substrate interactions and detoxification rates. Five rounds of iteration led to identification of highly active PTE variants that hydrolyze the toxic isomers of V-agents and G-agents; these new enzymes provide the basis for broad spectrum nerve agent detoxification. In conjunction with other computational redesign studies, this work will also serve to build a robust protocol for computationally aided enzyme optimization.
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Message 76670 - Posted: 29 Apr 2014, 21:44:14 UTC

This is a very useful news thread to learn about the latest developments in the field.
If you ever create a newsletter, please count me in too!
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Message 76724 - Posted: 14 May 2014, 18:19:07 UTC

I would love to be the recipient of a newsletter as well. Nice to see what all of those donated cycles are doing for the world :D
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Message 76725 - Posted: 14 May 2014, 21:05:32 UTC

\"Yes\" to more frequent, official updates.
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Message 76744 - Posted: 18 May 2014, 6:44:55 UTC

+1 to the newsletter
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Message 76745 - Posted: 18 May 2014, 7:05:43 UTC

Actively sending out a newsletter would definitely engage people a lot more!

A few times a year would be fine, but no more than once a month I think.
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