DISCUSSION of Rosetta@home Journal (3)

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David Baker
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Message 36905 - Posted: 17 Feb 2007, 6:13:58 UTC - in response to Message 36839.  

David,

Can't you send an e-mail to these contributors?

Kristof



I thought posting here was better to avoid bothering anybody who was no longer interested in the project.
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FluffyChicken
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Message 36906 - Posted: 17 Feb 2007, 8:33:13 UTC - in response to Message 36905.  

David,

Can't you send an e-mail to these contributors?

Kristof



I thought posting here was better to avoid bothering anybody who was no longer interested in the project.


My quick look through, show pretty much all of them are still returning results (well at least have RAC) so I would assume they are interested.

I personally would email them as per thie Newsletter emial preference.

In fact just send out a newsletter to all who allow it to be sent, with a little update and asking who they are.
That is why the newsletter feature is there.

Other projects send them out. (e.g. seti, WCG)
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Art Luke

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Message 37146 - Posted: 23 Feb 2007, 15:49:59 UTC - in response to Message 36643.  

Sorry for the oddball question, but are you the same Keith Akins that went to Penn State with me?
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Message 37194 - Posted: 26 Feb 2007, 4:56:53 UTC

I don't understand, “Creating an HIV vaccine is one of the great scientific challenges of our time,”:

Does this mean that someone with HIV will be cured, or that someone can be vaccinated against getting HIV (i.e. they don't have HIV, but can no longer get HIV), or that it will elicit an immune response in both (so cure and vaccinate at the same time)?
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David Baker
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Message 37196 - Posted: 26 Feb 2007, 5:30:26 UTC - in response to Message 37194.  

I don't understand, “Creating an HIV vaccine is one of the great scientific challenges of our time,”:

Does this mean that someone with HIV will be cured, or that someone can be vaccinated against getting HIV (i.e. they don't have HIV, but can no longer get HIV), or that it will elicit an immune response in both (so cure and vaccinate at the same time)?


vaccines work before a person is infected with a virus or other pathogen by priming the immune system to destroy the pathogen, after a person is infected is too late for a vaccine, unfortunately, as the battle with the pathogen has already started.

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hugothehermit

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Message 37227 - Posted: 27 Feb 2007, 5:00:49 UTC

vaccines work before a person is infected with a virus or other pathogen by priming the immune system to destroy the pathogen, after a person is infected is too late for a vaccine, unfortunately, as the battle with the pathogen has already started.


Thanks Dr D.B.

As I was unsure if the word vaccine meant something else to biochemists, chemists etc...

Dr. Kwong's group has determined how an antibody can neutralize the virus by binding to a critical region on its surface required for binding to and entering our cells


Is there any possibility that you could design a protein that would bind to this HIV site, just to interfere, not to cure, but as a life prolonging drug/protein?
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David Baker
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Message 37230 - Posted: 27 Feb 2007, 7:37:57 UTC - in response to Message 37227.  

vaccines work before a person is infected with a virus or other pathogen by priming the immune system to destroy the pathogen, after a person is infected is too late for a vaccine, unfortunately, as the battle with the pathogen has already started.


Thanks Dr D.B.

As I was unsure if the word vaccine meant something else to biochemists, chemists etc...

Dr. Kwong's group has determined how an antibody can neutralize the virus by binding to a critical region on its surface required for binding to and entering our cells


Is there any possibility that you could design a protein that would bind to this HIV site, just to interfere, not to cure, but as a life prolonging drug/protein?


Yes! We have been working hard on computational design of such an HIV inhibitor, and already have a candidate that look quite promising in silico. We should have experimental results on this designed protein in a couple of months.
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Message 37231 - Posted: 27 Feb 2007, 11:14:32 UTC - in response to Message 37230.  

Is there any possibility that you could design a protein that would bind to this HIV site, just to interfere, not to cure, but as a life prolonging drug/protein?

If you can bind to GP120 or wherever, and successfully inhibit the virus's entry into cells or it's hijacking of the cell's processes, meaning no more virus is produced, then wouldn't the existing virus be destroyed naturally anyway?

If so, would that therefore allow normal bodily processes to resume? (I don't believe HIV alters/inserts any DNA into the host's cells - doens't it just hijack the RNA transcription process?)
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Message 37243 - Posted: 28 Feb 2007, 4:20:44 UTC

Yes! We have been working hard on computational design of such an HIV inhibitor, and already have a candidate that look quite promising in silico. We should have experimental results on this designed protein in a couple of months.


That's excellent news.
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Message 37344 - Posted: 3 Mar 2007, 12:53:17 UTC

Where would the electrons in this reaction come from?:

2C02 + 2e- + H20 -> C2O3H2 + O2

cheers
Danny
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Message 37360 - Posted: 4 Mar 2007, 2:46:36 UTC - in response to Message 37344.  

Where would the electrons in this reaction come from?:

2C02 + 2e- + H20 -> C2O3H2 + O2

cheers
Danny

A huge car battery or a power station ? ;-)

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Message 37362 - Posted: 4 Mar 2007, 2:49:44 UTC


We have spent the last several days devising simplified biochemical cycles that would convert carbon dioxide into simple sugars using enzymes we would computationally engineer with your help on rosetta@home. Graduate student Justin Siegal and postdoc Eric Althoff have come up with a very clever new reaction cycle using new enzymes we would collectively engineer that in total carries out the following reaction:

2C02 + 2e- + H20 -> C2O3H2 + O2

the product is a simple sugar that could be used in a variety of ways, and the removal of C02 from the atmosphere would be great for countering global warming. A nice thing about this compared to current ideas of forming inorganic carbonate compounds is that it requires no other inputs. However, it does require electrons, and hence a source of energy. We are currently assessing the energy requirements of this process and comparing them to those of other proposed carbon sequestration mechanisms.



Is this a separate project from the Rubisco work mentioned in an earlier post? Whether it is or not it would be good to know how the work units are named. Its always interesting to know what the work units represent and their biological significance : any chance of keeping the Active WorkUnits log a little more up to date?

The goal of designing an enzyme from scratch in this way sounds very ambitious and quite a bit beyond the original scope of Rosetta as I understand it. Is there a model system to start with? Do you design an active site and then try and build a protein around it? More information on the steps involved would be most interesting.

Also: would such an enzyme or an improved version of Rubisco really have an impact on global warming? Unfortunately I suspect the answer is no : plants might grow a bit faster if carbon dioxide uptake happens to be the limiting factor for their growth but once they die and decay the CO2 will get released again into the atmosphere : it's not a permanent solution.

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David Baker
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Message 37372 - Posted: 4 Mar 2007, 7:48:53 UTC - in response to Message 37360.  

Where would the electrons in this reaction come from?:

2C02 + 2e- + H20 -> C2O3H2 + O2

cheers
Danny

A huge car battery or a power station ? ;-)


Yes--while we still have a lot of details to work out, and all the actual research is in the future (everything we are doing now is medically related), it is clear that a significant source of energy will be required. converting C02 into an organic compound with multiple carbon atoms is an energetically uphill process, and we can't change this.
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David Baker
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Message 37373 - Posted: 4 Mar 2007, 7:53:05 UTC - in response to Message 37362.  


We have spent the last several days devising simplified biochemical cycles that would convert carbon dioxide into simple sugars using enzymes we would computationally engineer with your help on rosetta@home. Graduate student Justin Siegal and postdoc Eric Althoff have come up with a very clever new reaction cycle using new enzymes we would collectively engineer that in total carries out the following reaction:

2C02 + 2e- + H20 -> C2O3H2 + O2

the product is a simple sugar that could be used in a variety of ways, and the removal of C02 from the atmosphere would be great for countering global warming. A nice thing about this compared to current ideas of forming inorganic carbonate compounds is that it requires no other inputs. However, it does require electrons, and hence a source of energy. We are currently assessing the energy requirements of this process and comparing them to those of other proposed carbon sequestration mechanisms.



Is this a separate project from the Rubisco work mentioned in an earlier post? Whether it is or not it would be good to know how the work units are named. Its always interesting to know what the work units represent and their biological significance : any chance of keeping the Active WorkUnits log a little more up to date?

The goal of designing an enzyme from scratch in this way sounds very ambitious and quite a bit beyond the original scope of Rosetta as I understand it. Is there a model system to start with? Do you design an active site and then try and build a protein around it? More information on the steps involved would be most interesting.

We do both: in some cases we start from scratch and in others we reengineer an already existing site. In this case we are thinking about starting with Rubisco and improving it for this application.

Also: would such an enzyme or an improved version of Rubisco really have an impact on global warming? Unfortunately I suspect the answer is no : plants might grow a bit faster if carbon dioxide uptake happens to be the limiting factor for their growth but once they die and decay the CO2 will get released again into the atmosphere : it's not a permanent solution.

but if the cycle can be made to go in a completely artificial system the fate of the products can be controlled.



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Message 37740 - Posted: 13 Mar 2007, 0:15:37 UTC

Rosetta 5.51 adds the ability to model RNA. How is modelling RNA different from the protein modelling we've been doing? Aren't the amino acids and atoms involved the same? Are the assumptions about hydrophobic and hydrophilic portions of the chain still used?

How will the ability to accurately predict the structure of a strand of RNA be used in science and medicine? Isn't RNA in the interior of cells? And therefore more difficult to create a docking agent for?
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Message 37835 - Posted: 15 Mar 2007, 4:40:56 UTC - in response to Message 37740.  
Last modified: 15 Mar 2007, 4:41:22 UTC

Hi Feet1st, I've tried to motivate the new RNA efforts at this post. To answer your specific questions, the basic monomeric unit in RNA ("a nucleotide") is actually rather different from that of a protein. So, the energy function (i.e., what parts we try to stick together) is somewat different from proteins, and involves thinking instead about the kinds of physical forces that Watson and Crick used to decipher DNA structure. For example, in these simulations, base stacking and base pairing are rewarded -- such forces are not quite the same as the forces between ring-like protein sideachain, though deep down, they turn out to be manifestations of the same hydrophobic effect and hydrogen bonds that mediate protein folding.


Rosetta 5.51 adds the ability to model RNA. How is modelling RNA different from the protein modelling we've been doing? Aren't the amino acids and atoms involved the same? Are the assumptions about hydrophobic and hydrophilic portions of the chain still used?

How will the ability to accurately predict the structure of a strand of RNA be used in science and medicine? Isn't RNA in the interior of cells? And therefore more difficult to create a docking agent for?


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Message 37921 - Posted: 17 Mar 2007, 16:31:41 UTC

I have two questions.

1. If RNA is similar to DNA then doesn't the energy question become more comlex
Doesn't DNA both fold and coil to a reletive high energy state?

2. As far as protiens go, if the N-Terminus folds first (the protien folds as it
is built), then are N-Terminus jobs comming in the future?
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Tom Philippart
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Message 40053 - Posted: 29 Apr 2007, 16:34:16 UTC - in response to Message 37921.  
Last modified: 29 Apr 2007, 16:54:48 UTC

Suggestion:
I think there should be a section on the front page with a list of all the papers published (including a pdf of it) seeing that there are some papers in the works.
Maybe you could also use the Articles section for this purpose.
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Message 40063 - Posted: 29 Apr 2007, 19:05:27 UTC

i think that's definitely a good idea...
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Message 40462 - Posted: 7 May 2007, 3:08:32 UTC - in response to Message 37921.  

Sorry, this is a late reply. The good news is that both RNA and DNA tend to go to its low energy state. Natural DNA strands tend to come with their complementary partners and form the double helices you always see cartoons of. But you're right the energy question can become more complex -- RNA is infamous for getting stuck in higher energy metastable states, as you suggest. Indeed, one of the eventual applications of this algorithm is to attempt to infer what these mysterious states look like.

Regarding proteins folding from the N terminus, its a bit complicated. Although proteins in cells are created from the N-terminus first, they are also surrounded by chaperones, and make potentially important contacts to the protein-creation machinery (the ribosome). So you might think its all a bit complicated -- but then the "thermodynamic hypothesis" comes to the rescue. Many (maybe most) single domain proteins appear to refold even after being fully denatured by heat, in the absence of any other machinery. So the lowest energy state of the full chain really does appear to be well defined, and our simulations aim to capture that.

That being said, we've discussed writing code to simulate folding from one end first, but no one has got around to it!

I have two questions.

1. If RNA is similar to DNA then doesn't the energy question become more comlex
Doesn't DNA both fold and coil to a reletive high energy state?

2. As far as protiens go, if the N-Terminus folds first (the protien folds as it
is built), then are N-Terminus jobs comming in the future?


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