Subject: Re: CCL:summary of data analysis of protein structures

From: Charles Letner <[email-masked]>
Date: Tue, 21 Feb 1995 08:25:26 -0800 (PST)

Hello Sandeep and others,
	Thank you for compiling and posting your summary.  There are two
points that I think need to be concidered.

> ...
> 2) One could try to predict molecule's structure with force
> filed calculations: too slow even for small molecules. 
> ( paramatrisation of MD programs takes a LOOOOOOOOOOOOOOOOOOOONG time. 
>  only large companies, consortia etc. ( BIOSYM/SanDiego) can cope with
> that.)
> 3) MD is, in principle just an inadequate method. 
> why shold f.i. 2 H behave differently in the same distance from each
> other when they have a different ditance along the backbone? 
> ... 
	One of the basic assumptions of typical force fields is that you
can Hooke's law to model bond lengths, ie:
	
		E = K(r-req)^2

where E is the energy, K is constant controlling the "stiffness" of the
bond, r is the distance, and req is the ideal distance (K and req are the
parameters for this term of the force field).  Note that this is a
parabola with it's minimum at req.  This is different than reality.  At
long bond lengths this energy continually increases.  In reality the bond
breaks.  Similar arguments can apply for the other typical terms.  The
point is that these force fields are ment to deal with systems that are
close to the structure you are interested in modeling.  Ie/ you can't take
a long chain of amino acid residues and expect it to fold into some kind
of meaningfull conformation.  This is not to say in the limit of infinite
time you might not find the conformation you are looking to find.  Now if
you have some previous knowledge of the conformation, ie/ high homology
with another protein who's strucuture has been deteremined, you are
playing a different game.  SO, to use MM/MD to try and get the structure
of a protein given no other info than it's primary sequence is probably an
inaprorpriate use of the method.  On the other hand, if you have some
structural info it may be apropriate, ie/ you can at least make a
"resonable" guess at what the strucutre is.  

> 4) if you work with ab initio-methods to fit data, they take an even
> LOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOnger time to fit fro small molecules. 
	True.  However, I'm not sure that many people (is ANYONE) are
trying to apply ab initio methods to protein structre.  MAN would I love
to have access to the machine that can run Gaussian on say 1000 atoms (the
size of bpti, a small protein).... msec MD here I come!  8)

	A method that was not mentioned was genetic algorithms.  I've seen
some interesting results with GA's towards the problem of structure
prediction.  However, I can't say much else about them.  It is probably
worthwhile to mention Chow/Fasman, hydropothy plots, etc as more
classical methods of structural prediction.  Chow/Fasman did look at a
large number of protein structures to come up with their empirical values.
 See Cantor and Schimmel (1980) volume 1 for more info. on these ideas.

>Thiis board is still viewed by many as quantum chemistry and hence is
>probably not widly followe by protein crystallographers.Subscribe to
>bionet.xtallography on you nearest internet newstand and send them your
>request. 
	I expect this is true.  But hey, there are a few renegade
biochemist roaming this board...  So stick around!  Who know's maybe we'll
convert all these chemist to biologist yet....  Oh ouch those flames are
kill'n me!   8-)    Or maybe it's the other way around.  Anyhow, physicist
say we are all evolving into physicist......
Bye,
Chuck

Charles Letner
Wright State University
Department of Biochemistry
Dayton, OH 45435
e-mail: [email-masked]