From: Eugene Leitl (Eugene.Leitl@lrz.uni-muenchen.de)
Date: Fri Apr 18 1997 - 13:14:21 MDT
On Fri, 18 Apr 1997, ard wrote:
> We have some questions which we would love to get some feedback on if
Let us swap some good antihelmintica urls.
> there is anyone on the list who is familiar with the problem.
PFP/iPFP? _The_ most trivial problem of entire molecular biology.
> The overall question is how a protein with a certain sequence of amino
> acids takes the form of a unique three dimensional structure in water/body.
Actually I think the inverse problem is much more interesting. (I
also think it also to be much harder).
> The next level of question to this, what are(is) the most dominating
> forces in the formation of the unique structure. In the 60's an oil drop
The most dominating? Volume exclusion. At biological energy levels no two
atoms may occupy the same place. Second by stringence: no covalent bond
may break (ignoring autocatalytical scissile bond activity, which is Rare).
> in water was suggested and said as the oil in water collapses to a globule
> so does a stretched sequence of protein collapses into a globular-like
Uh, it is more than crude. It is an important contribution, but without
other's contribution impact your Hamiltonian is entirely bogus.
> structure. This force was/is called hydrophobicity. Later on it was found
> that water around oil/apolar groups in proteins forms very organized
> structures known as clathartes/ice-like structures etc. These "ice-like"
Clathrate domains are long and well known structures. In fact water has
nanoscopic, fluctuating ice domains. Methane/water clathrate is very well
known due to its propensity to clog up siberian gas pipelines. Modeling
methane aggregation in a water box is very well known PFP toy model.
> structures have small entropy (high structure) Until recently the
> understanding was up to this point: formation of highly organized
> structures around apolar groups. Recently it has been found that the low
> entropy phenomena is not restricted to apolar groups but is found for water
> around polar groups as well. So what do we do? What is so unique about
PFP people are a heterogenous field, there is very little dogma there.
> water around polar groups (oily matter)? It has been found it the past few
> years that the heat capacity (tendency to absorb heat) around apolar groups
> increases while the heat capacity of water around polar groups decreases.
> Can this last observation be reproduced by computer simulations? Can this
> be explained by a reasonable theory?
Why is heat capacity of such an interest to you? _Which_ heat capacity?
Besides, I doubt heat capacity has much relevance in nanocluster domain.
Modeling? Sure you can model that.
> If it is understood how water behaves around apolar groups and polar
> groups in proteins, it will be easy to understand and predict the formation
> of a unique 3-dimensional structure from a sequence of protein. Hence the
Oh no. You forgot the oompteen other contributions. Trivial example: two
helices interact strongly, being macroscopical dipoles. And water is not
the only context, what about phospholipid bilayers? Assymetric bilayers?
How about influence of protein history upon tertiary structure?
Disulfides require certain redox potential, and chaperonines have some
crucial aspects to the fate of misfolded proteins. Being under kinetical
control, ribosome outlet channel/transmembrane transport protein pore
geometry has a distinct impact on tert structure.
Context is crucial: in vivo may fold different from in vitro.
> design of a drug from a computer for a diseased protein.
Easy it is not. PFP, and particularly IPFP require dedicated hardware and
novel algorithms to be usable. Coming soon to a site near you.
> We would appreciate any discussion of this problem.
Let's discuss antihelmintica instead. Tapeworms are fascinating creatures.
> ard
>
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