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:
I can see I won't be able to persuade you that kinetics might
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
>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.
>What are your arguments against hydrogen bonding "directing" folding?
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
| ,_ 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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