QUESTIONS: alpha-helix "signals" in proteins

Simon Brocklehurst Bioc smb18 at mole.bio.cam.ac.uk
Wed Jul 6 06:17:46 EST 1994

kenp at banyo (Kenneth Prehoda) writes:

Excellent, some debate at last on this newsgroup!
(Let's keep it light hearted though!!!)

So to take some of the points you made:

>Simon Brocklehurst (Bioc) (smb18 at mole.bio.cam.ac.uk) wrote:
>: Ken Prehoda <kenp at nmrfam.wisc.edu> wrote:

>: >Since protein folding is believed to be thermodynamically controlled

>: Errr... NOT!

>What is the problem with my statement.  The current consensus is
>that protein folding is thermodynamically controlled.

  The problem is that there is simply not a consensus!

>  It is true
>there are dissentions from the consensus, but when is that not
>the case?  If you believe otherwise, please provide references (and
>not quotes from Wayne and Garth as you seem to prefer). I refer
>you to reviews by Baldwin & Kim, Dill, and many others.

  I'll quote some experiments/refs below.
(stuff deleted)

>Of course a folding pathway is involved in going from the unfolded
>state to the native state.  That's a given.  Whether or not
>the pathway determines the structure is a very different question.

      What about the work of Fersht's group, Dobson's group etc.
There seems to be a compulsory order by which bits of structure form on
folding pathways of different proteins.  For many proteins,
highly populated kinetic intermediates seems to exist on folding
pathways (although there is some recent debate about this [see
Englander and coworkers]).

       Thus it seems probable (to me at least) that only kinetically 
accessible energy minima will be found on the free energy surface. 

    Given all this, I don't see why you are so dismissive of the
idea that kinetics are important in protein folding.
>:   As for the original point about the relatiave importance of secondary  
>:   vs tertiary vs intrinsic interactions, for controlling formation of 
>:   (secondary) structure:

>Could you please explain what you mean by "intrinsic" interactions? If
>you are refering to the so-called helical-propensity, then how can
>you distinguish between secondary, tertiary and intrinsic interactions?

  1) Intrinsic propensity

     Some people think that particular residues have intrinsic 
     propensities to exhibit particular conformations.  For
     example, you will find many references in the literature
     saying that alanine residues are strongly helix forming.

     This propensity could be due to the wave function for
     alanine.  Certainly, it is often difficult to identify
     (from inspection of 3-D structures) inter-residue interactions 
     involving surface alanine residue that could be regarded as
     strongly stabilizing.

  2)  Secondary and tertiary interactions

      The distinction is trivial.  Stabilzing inter-residue
      interactions made within a given secondary structural motif
      are secondary interactions. Others are tertiary!

      The question of the point on the folding pathway that
      interactions become native-like is vigourously debated.

     (stuff deleted)

>:   But, it is worth remembering that the so-called "hydrophobic effect"
>:   is most likely to be the major driving force in structure formation.

>Depending on your definition of the hydrophobic effect, this is highly

      Well it doesn't matter how _I_ define it! The point is that,
somehow, it seems likely that intra/inter molecular interactions
involving hydrophobic groups are important in directing folding.

     I agree that there is debate is some quarters about this. But
a lot of the other suggestions (e.g. main-chain hydrogen bond formation
directs folding) are just nonsense.

(well it is debatable regardless of your definition, but
>without knowing what you mean by the hydrophobic effect I cannot
>argue the point).

     Sure you can!  Just say what you think the driving force for
finding the native state is (with particular emphasis on things
not involving hydrophobic groups).

 |  ,_ 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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