QUESTIONS: alpha-helix "signals" in proteins

maglor at maglor at
Mon Jul 11 07:35:53 EST 1994

>  ------<Huge Amounts of Stuff Deleted>---------
>  After all this, I still don't understand the businees about the
>"folding pathway being irrelevant to the native state".  I would
>like to ask everyone (Ken particularly) this question:
>       Do people out there think that the GLOBAL energy minimum
>conformation of a polypeptide chain is the native folded conformation
>that we observe?
>       If not, why does it matter whether protein folding is
>thermodynamically controlled or kinetically controlled?
>  The final question I would like to ask is: what bearing do these
>arguments have for predicting the three-dimensional structure of
>a protein for it's amino-acid sequence?
>   Sorry for the length of this post - but I hope some things are
>a but clearer now!
>|  ,_ o     Simon M. Brocklehurst,
>| /  //\,   Oxford Centre for Molecular Sciences,
>|   \>> |   Department of Biochemistry, University of Oxford,
>|    \\,    Oxford, UK.
>|           E-mail: smb at
This thread has been extremely interesting but people are distinctly talking
at cross purposes.  The question of thermodymamic vs kinetic control of 
folding seems to have been lost in the ongoing entrenchment of positions.
Point for thermodynamic control:
1) High energy states are unstable, therfore lower energy states are favored.
Point for kinetic control:
2) It can take a long time to get to the lower energy states.

Do these points imply that that there is only one low energy state?  No, there 
can be mutiple states all in equlibrium with each other.  Do these points imply
that the transition to the lower energy state is rapid?  No, it says nothing
about the rate of the reaction.  People seem to be forgetting basic chemistry.
When dealing with a chemical equlibria it is necessary to determine both the 
equilibrium constant _and_ the rate constant.  This means that for the folding
of proteins, neither the pure _kinetc_ or the pure _thermodynamic_ control will
completely discribe the phenomena of protein folding IN ALL CASES.  There are
undoutably proteins which due to the rate constant of folding are trapped in 
some relatively high energy state.  But it is equally likely that there are 
proteins which proceed rapidly down their folding pathway to the low energy
state.  This brings me back to the question of whether or not studying protein
folding is important.  The answer to this has to be yes.  Since it is possible
to trap folding intermediates, and it is possible that the _rate_ of the 
folding reaction is such that higher energy states could be trapped in vivo 
and in vitro, the studying of protein folding is worthwhile.  Finally, for
predicting 3-D structure I feel that this argument has some but limited bearing.
Realistically, even the highest energy "kinetically trapped" structures will
probably have energies and conformations very similar to the GLOBAL MINIMUM.
Therefore, if we can develop methods for rapidlly predicting these minimum 
energy structures from the amino acid sequence we will gain insight into both
the kinetic and the thermodynamic aspects of protein folding.
* Mark Trumbore                                                               *
* Biomolecular Structure Analysis Center                                      *
* University of Connecticut Health Center                                     *
* Farmington, CT 06030-2017                                                   *
* Phone: (203)679-4315; Fax: (203)679-1989; Email: Maglor at       *

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