QUESTIONS: alpha-helix "signals" in proteins

Simon Brocklehurst Bioc smb18 at mole.bio.cam.ac.uk
Wed Jul 6 12:11:26 EST 1994


Ken Prehoda <kenp at nmrfam.wisc.edu> writes:

 (stuff deleted)

  I can see I won't be able to persuade you that kinetics might
be important!  

As an aside to your point about  keeping proteins in jars on benches.
I'm sure you know that a lot of enzymes loose activity over time.
Some people have postulated that when this happens, the proteins are 
going into a deep energy minimum, becoming less flexible, and thus 
loosing activity.

>Like I said before, I cannot see a distinction between "intrinsic
>propensity" and secondary,tertiary interactions.  Let's take as an
>example alanine which has a high helical propensity.  Why does it
>have a high helical propensity?  The most likely explanation is that
>it does not have a gamma constituent to provide steric constraints.

  Why would the absence of a gamma constituent make alanine residues 
helix forming, as opposed to beta-strand forming, as opposed to irregular 
conformation forming, as opposed to more flexible than larger amino-acids 
etc etc?  There is plenty of space on the surface of helices to allow
large-side-chains to rotate rapidly in solution.

(stuff deleted)

>What are your arguments against hydrogen bonding "directing" folding?  

  Here goes:

  1) There is no thermodynamic (!!) advantage for main-chain polar groups
     to make intramolecular hydrogen bonds rather than to make hydrogen
     bonds with solvent -- is there?

  2) Unfortunately, for many proteins whose folding pathways have
     been studied so far, it has not been possible to tell if hydrophobic 
     collapse occurs before or after the formation of stable, 
     long-lived hydrogen bonds.  In one case (the protein interleukin
     1-beta) , though, it was possible to tell: the interpretation is 
     difficult, but it seems that hydrophobic collapse occurs _before_ 
     the formation of long-lived, stable hydrogen bonds.

   3) Every amino-acid residue (except proline) has the same main-chain
      capacity to form main-chain hydrogen bonds - it's the side-chains
      that provide the variation. i.e. the sequence of the protein
      directs it to fold.

   4) Hydrogen bonds involving surface side-chains seem to be important
      at the ends of secondary structural motifs - so-called caps.
      But these are not that highly conserved across homologous
      families: thus they probably don't drive the folding of the
      protein.

 _________________________________________________________________________
 |
 |  ,_ o     Simon M. Brocklehurst,
 | /  //\,   Oxford Centre for Molecular Sciences,
 |   \>> |   Department of Biochemistry, University of Oxford,
 |    \\,    Oxford, UK.
 |           E-mail: smb at bioch.ox.ac.uk
 |________________________________________________________________________





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