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Author Topic:   Protein folding, the origin of novelty and everything
Tranquility Base
Inactive Member


Message 1 of 7 (13617)
07-16-2002 3:23 AM


Protein folding finally gets its own thread! Let no-one ever again think of genes as simply lists of A, G, C and Ts!

Here is a great mainstream web site explaining protein folding and protein folds (we have talked a lot about this in various threads around here):

http://www.lmb.uni-muenchen.de/users/steipe/lectures/structure/node03.html

For example we see that estimates put only about 1 in 10,000 random sequences folding at all and of course these would be non-functional. So a new gene starting from random DNA (or drastically altering fold from an existing gene) has to fight this sort of barrier even before it can begin to be selected for. After chancing on to a foldable sequence it still has no function so it will drift away from the foldable sequence.

PS - for any protein newbies here, proteins are what genes code for and they make the world go around by doing all of the structural, catalytic, signalling, detecting, transport, motor and metabolic funcitons of the cell either directily or after making a non-protein chemical to do the job. They only do this job if they have (i) a foldable seqeunce, (ii) have an active or catalytic site and (iii) this biochemical function is useful in some cellular context.

On this web page you can find some beautiful schematics of protein folds (scroll to bottom):

http://www.lmb.uni-muenchen.de/users/steipe/lectures/structure/node04.html

Here is the web site where structural biologists deposit these 3D datasets determined by X-ray crystallography and NMR (predciton from seqeunces is an ongoing struggle but progress is being made):

www.pdb.org

although here is probably a better site where one can peruse all of the known folds via the "CATH" catalog:

http://www.biochem.ucl.ac.uk/bsm/cath_new/class.html

Here is a rather impressive prtoein fold (click on image for a larger view, alpha-helices are magenta and beta-strands are yellow):

http://www.biochem.ucl.ac.uk/bsm/cath_new/domains/3aahA0.html

(The amazing thing is that just about every individual molecule with that sequence will fold to that exact shape so that it can do a very specific job.)

Here's another fold:

http://www.biochem.ucl.ac.uk/bsm/cath_new/domains/1lxa01.html

and one more:

http://www.biochem.ucl.ac.uk/bsm/cath_new/domains/1rie00.html

And here's how the cell makes proteins from RNA copied from DNA on a gene:

http://www.accessexcellence.org/AB/GG/protein_synthesis.html

The ribosome that reads the RNA and strings the amino-acids of the protein together (green in the previous link) is itself an association of about 50 proteins and RNA:

http://www.molgen.mpg.de/~ag_ribo/ag_franceschi/

So sometimes, the ribosome unknown to itself, is making more of itself. Here is a rotating model of the 50S half:

http://www.molgen.mpg.de/~ag_ribo/ag_franceschi/franceschi-projects-50S-2.html

Each of the colored bits is a folded ribosmal protein required to make the ribosome translate RNA into protein. The gray is structural RNA (not the RNA that is translated). Here is the other half of the ribosome complex:

http://www.molgen.mpg.de/~ag_ribo/ag_franceschi/franceschi-projects-30S-2.html

[This message has been edited by Tranquility Base, 07-16-2002]


Replies to this message:
 Message 2 by John, posted 07-16-2002 10:07 AM Tranquility Base has not yet responded
 Message 3 by derwood, posted 07-16-2002 1:02 PM Tranquility Base has responded
 Message 5 by Brad McFall, posted 07-26-2002 11:57 AM Tranquility Base has responded

  
John
Inactive Member


Message 2 of 7 (13624)
07-16-2002 10:07 AM
Reply to: Message 1 by Tranquility Base
07-16-2002 3:23 AM


quote:
Originally posted by Tranquility Base:
Protein folding finally gets its own thread!

whoooo-hoooooo!!!!

Let me read this stuff. I'll be back. This should be fun.

------------------
www.hells-handmaiden.com


This message is a reply to:
 Message 1 by Tranquility Base, posted 07-16-2002 3:23 AM Tranquility Base has not yet responded

Replies to this message:
 Message 7 by Lord Parsimony, posted 12-05-2002 4:18 AM John has not yet responded

  
derwood
Member
Posts: 1457
Joined: 12-27-2001


Message 3 of 7 (13632)
07-16-2002 1:02 PM
Reply to: Message 1 by Tranquility Base
07-16-2002 3:23 AM


Interesting - from the first link, we see that any given fold can be encoded by some 10^10 different serquences.

"If we exclude detectable “homology” -for a sequence of length 100, on the order of 10^113 sequences exist that are > 20 % identical - we still remain with 10^10 distinct, foldable sequences for each fold."

Emphasis mine.

That site also mentions the bit about random sequences (TB was correct). Of course, when one neglects to mention the parameters, big numbers are impressive. When one considers that selection is not random, and that genes encoding useful proteins would be selected for, those numbers are moot.


This message is a reply to:
 Message 1 by Tranquility Base, posted 07-16-2002 3:23 AM Tranquility Base has responded

Replies to this message:
 Message 4 by Tranquility Base, posted 07-16-2002 8:39 PM derwood has not yet responded

    
Tranquility Base
Inactive Member


Message 4 of 7 (13671)
07-16-2002 8:39 PM
Reply to: Message 3 by derwood
07-16-2002 1:02 PM


^ I agree selection is not random but the generation of sequences to be selected is so the 1 in 10,000 holds. The point is that before selection can even start to come into play the estimate is that there is a 1 in 10,000 hurdle. This statement is not reversed by the fact that 10^10 seqeunces can fold to the same topology. 10^10 is nothing compared to the 20^100 possible sequences!

The point is that there is a very sharp discontinutiy between mutations optimizing existing genes and generating new folds! it is the reason why we don't see new protein families in the lab or in the field. It is the reason why no-one expects the Galapogos finches to be dsintinguishable by protein families. It doesn't make macroevoltuion impossible automatically but it shows that evidence for microevolution is almost irrelevant.

[This message has been edited by Tranquility Base, 07-16-2002]


This message is a reply to:
 Message 3 by derwood, posted 07-16-2002 1:02 PM derwood has not yet responded

  
Brad McFall
Member (Idle past 3144 days)
Posts: 3428
From: Ithaca,NY, USA
Joined: 12-20-2001


Message 5 of 7 (14218)
07-26-2002 11:57 AM
Reply to: Message 1 by Tranquility Base
07-16-2002 3:23 AM


TB,

Given that synthetic chemistry can produce tommarow something that is not here today the problem as you have re-threaded it, seems to me to ask if out of the possible NUMBER of protein fold positions, is there really any biological reason to think we need consider them all. What if the ICR model remanded that we consider every location of an electron on the INTERIOR of the metal it is communicated on? From the concept of reproductive doubling we seem to be at a loss to virtually at least subtract off that which is not in truth real??


This message is a reply to:
 Message 1 by Tranquility Base, posted 07-16-2002 3:23 AM Tranquility Base has responded

Replies to this message:
 Message 6 by Tranquility Base, posted 07-28-2002 9:15 PM Brad McFall has not yet responded

    
Tranquility Base
Inactive Member


Message 6 of 7 (14332)
07-28-2002 9:15 PM
Reply to: Message 5 by Brad McFall
07-26-2002 11:57 AM


Brad

The all folds estimate comes from the ones we've seen and looking at how much of the human genome is left (with unknown folds) so it is not from biological necessity but empericism. It is like sampling a poulation and estimating the result if we could exhaust the population.

As usual I don't understand about half of your post!
1. What is the ICR modelyou are talking about?
2. How could eletrons and metals have anything to do with protein folding?
3. What is reproductive doubling?


This message is a reply to:
 Message 5 by Brad McFall, posted 07-26-2002 11:57 AM Brad McFall has not yet responded

  
Lord Parsimony
Inactive Member


Message 7 of 7 (25532)
12-05-2002 4:18 AM
Reply to: Message 2 by John
07-16-2002 10:07 AM


Read? Read stuff? What's there to read? Don't you have any backbone, sequentially speaking? Who needs proteins when, if you've got any backbone, you can use enzymes?
This message is a reply to:
 Message 2 by John, posted 07-16-2002 10:07 AM John has not yet responded

  
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