QUESTIONS: alpha-helix "signals" in proteins
kenp at banyo
Thu Jul 7 13:23:05 EST 1994
Simon Brocklehurst (Bioc) (smb18 at mole.bio.cam.ac.uk) wrote:
: Maybe we're talking at cross purposes, 'cos I should have
: thought that this is extremely relevant to the kinetic/thermodynamic
: >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???
: They're kinetically inaccessible. That is, if you don't have
: transition states of sufficiently low energy to allow the protein to
: pass through them, then you won't get to a particular energy minimum
: (native state).
That's my point - they're kinetically inaccessible (in most cases) if
they are there at all. So of what importance are they? To put it
another way, do you believe it is valid to use equilibrium constants
when studying protein systems?
: >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.
: Well in alpha helices i,i+4 side-chains are close in
: space, and you do observe a limited number of time-averaged side-chain
: conformations in such positions (I think Mike Sternberg did some analysis
: of side-chain dihedral angles a while back - in J. Mol. Biol. ?).
: But these 'restrictions' do not cause a big problem for helix formation,
: because there are plenty of conformations available that are
Well, the researchers in the field that I have talked to believe
that these restrictions do cause energetic differences which is
one contribution the the "propensity."
: >: (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.
: Do you know that whether any/all of these suggestions are correct?
I wish. See Gellman et al. for extensive discussions. My point
is that the role of hydrogen bonds in protein stability is
entirely _uncertain_ in contrast to your strong opinion otherwise.
For one thing, how do you measure the strength of a hydrogen bond?
: | ,_ 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 nmrfam.wisc.edu
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