QUESTIONS: alpha-helix "signals" in proteins

Ken Prehoda kenp at nmrfam.wisc.edu
Wed Jul 6 10:45:00 EST 1994

In article <2ve3sq$68q at lyra.csx.cam.ac.uk> Simon Brocklehurst,
smb18 at mole.bio.cam.ac.uk writes:
>Excellent, some debate at last on this newsgroup!
>(Let's keep it light hearted though!!!)

Sounds great, but I would appreciate it if you practiced what you
preached.  Specifically comments like "Errr....NOT!" can be take a
number of ways, some of which may be insulting.

That said...

>>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!

Well let's look at one example (which is among many): the *widely
cited* review by Ken  Dill in Biochemistry (Dill, K. (1990)
Biochemistry 29, 2357).  Dill concludes that the thermodynamic
hypothesis can be taken as a given.  As I stated in my original
reply, there are disagreements over this.

>      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.

Even if there is a compulsory order to protein folding, this does
not disprove the thermodynamic hypothesis.  Neither does folding

Even so, I stick my neck out so far as to say who cares if protein
folding is kinetically controlled?  If protein folding is kinetically
controlled, it means that if we place a jar of protein on our lab
bench, it will eventually find that global free energy minumum.
Has this been observed?  Not to my knowledge.  Now the rate constants
may be so small that it will just may take lifetimes or more to observe.
Even so, to me this says that for all _practical_ purposes there is
thermodynamic control.

>>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

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.
If so, then this cannot be separated from secondary or tertiary

>>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.

Just like the genetic information of the cell being contained in DNA
is nonsense <place any other widely held belief that was debunked

What are your arguments against hydrogen bonding "directing" folding?  
While I personally agree with you that the "hydrophobic-effect" is the
dominant contribution to protein stability, there are some very
compelling arguments for hydrogen bonding.  If you are not aware of
these, and are interested, please let me know.

As for your definition of the hydrophobic effect, it is very important
since you may be discussing the price of tea in China while I am
complaining about Apple's stock price.  OK, this is obviously getting
too long so the hydrophobic effect will have to come in a later

> |
> |  ,_ 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

-Ken Prehoda
kenp at nmrfam.wisc.edu

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