QUESTIONS: alpha-helix "signals" in proteins
kenp at banyo
Wed Jul 6 13:59:57 EST 1994
Simon Brocklehurst (Bioc) (smb18 at mole.bio.cam.ac.uk) wrote:
: 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!
Let's look at what you are saying in a little more detail. I
assume you are saying there is some state which has a free
energy lower than our observed "native" state. However, this is
really irrelevant. Between the native and unfolded states
thermodynamic control still holds (i.e. it is path _independent_).
I don't see how you can argue that the folding pathway is
important without having multiple native states. Where are
these other states???
: 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.
Good point - one that I carefully neglected to mention ;-) But
for now, it is anybody's guess what is happening here.
: >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.
My impression is that i,i+4 side chains have steric interactions. This
is from discussions with members of Baldwin's group - I can't refer
to any paper's, although they're supposedly out there. You can
easily envision this with a little molecular modelling, though.
: (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?
How do you know this? You are assuming amide-amide hydrogen bonds
are equal in strength to amide-water hydrogen bonds. Additionally,
you are neglecting any cooperativy considerations that may be
present. For example, and entropic advantage for hydrogen
bonds is that once one h-bond is formed adjacent hydrogen bonds
no longer must pay that entropic cost. An possible enthalpic
advantage is that once one h-bond is formed, adjacent amides
become more polarized resulting in a more favorable enthalpy.
Both of your assumptions are questionable.
: 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.
So? what does this have to do with the thermodynamic stability of
the protein? The pathway does not determine the stability, but
instead, it is the end states. I hope you aren't arguing against
: 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
kenp at nrmfam.wisc.edu
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