Subject: CCL:summary:Protein Structure Prediction

From: Shubin Liu <[email-masked]>
Date: Fri, 17 Feb 1995 10:00:19 -0500 (EST)

Dear all CCLers:

A few days ago I inquired here the status and methods of protein 
structure prediction. I received many responses the details of which are 
enclosed. Special thanks are due to all the responsers, namely:
	John M. Sauder
	Eric Bittner
	Jeffrey L. Nauss
	Kaiqi Chen
	J. Mike Sauder
	Lin Dawei
	William T. Winter
	Eric Bauer
	Stanley Krystek
	Bob Funchess
	Marketa Zvelebil
	Bill Tivol
	Stanley Krystek

Shubin
.............................................................................
Shubin Liu
Department of Chemistry			    Email: [email-masked]
University of North Carolina		           [email-masked]
Chapel Hill, NC 27599-3290		    Tel  : (919) 962-0150(O)
.............................................................................

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From: John Michael Sauder <[email-masked]>

	I saw your posting on the biophysics newsgroup.  It wasn't clear
whether you were talking about predicting secondary structure or tertiary
structure.  
	There are algorithms that predict possible secondary structure 
(alpha helices, beta strands) based on the primary structure (the amino acid
sequence).  These algorithms are, of course, not 100% correct, but can 
usually give a general idea of what secondary structural elements might be
present in a protein.  This method can be coupled with a comparison of proteins
with known structure.  If their amino acid sequences are similar, their 
secondary structure will most likely also be similar.

	Predicting the tertiary structure (how the secondary structure fits
together to form the final folded structure) is much more complex.  Two 
methods are possible:  (1) Compare the amino acid sequence with other proteins
whose tertiary structures have been solved by x-ray crystallography or NMR
distance geometry calculations.  If the primary sequences are similar 
(at least 40-50% homologous), an attempt can be made to "build" the unknown
protein based on the structure of the known protein.  As the homology of the
two sequences decreases, the reliability of this method also decreases.  If
two sequences are, say, 80% homologous, you could be very certain of the 
predicted structure of your unknown protein.  However, if the homology is
less than 40-50%, it is often uncertain whether or not your prediction is
at all reliable.
	The second method involves a deep understanding of all the forces
involved in keeping a protein in its native (folded) state, such as van der
Waals interactions, electrostatic and hydrogen bonding interactions, 
allowable bond distances, bond angles, and dihedral angles, etc.  Parameters
representing all of these factors can used to create an energy function which
a computer can use to try to predict the protein structure.  The computer time 
required to do the calculations is very large, and the imperfection in the 
energy function and accompanying parameters makes this method very ineffective.
It will probably be decades before this approach is feasible.
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From: Eric Bittner <[email-masked]>

Peter Wolynes and co-workers have devoted a great deal of attention to
this problem.  Wolynes and Frauenfelder wrote a "Physics Today"
article about a year ago on the topic of protein folding (Feb 1994
issue of Phys. Today).  Since Peter and Hans are certainly the world
experts in this area, I'd suggest communicating directly with either
of them.

E. R. Bittner
Univ of Texas
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From: "Jeffrey L. Nauss" <[email-masked]>

You really need to check the literature first.  A simple search should
have uncovered several references.  There are many algorithms out
there to predict secondary structure, Chou-Fasman, Garnier, etc.  Some
(if not all) have been made into computer programs which are available
in the public domain.

Now if you are looking for how the secondary structural elements fold
into a tertiary structure, that is entering the protein folding
problem.  Again it has been discussed extensively in the literature
with several programs discussed.  Don't have any readily available as
it is outside my area but I know they exist.  

Keep in mind that neither the secondary or tertiary structure
prediction methods are very accurate.  For the secondary prediction
methods the best I have seen are about ~70% accurate.
 
						Jeff Nauss
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From: "mark w. dalton" <[email-masked]>

Hi!  Yes, there are quite a few programs for secondary structure prediction
or proteins.

Some are:
Antheprot:
                        [email-masked], [email-masked]
 
      This is a general annoucement of the availability of ANTHEPROT  to all
academic  researchers. ANTHEPROT (ANalyze THE PROTeins) is a package to make
protein sequence analysis such as alignment, secondary structure predictions,
sites & function detection,  physico-chemical profiles,  homology search and
3D display of protein structures.   This program is now available either for
IBM  RISC 6000 workstations  or  IBM PC compatible microcomputers.  The main
feature  of  ANTHEPROT  is that it is fully interactive  within  a graphical
interface. No particular knowledge about  computers is  needed and any mole-
cular biologist is able to use it.

SeqSee - Science( 258:p1369)
        or ftp canopus.biochem.ualberta.ca
        A suite of programs for protein sequence analysis

ProfileScan- forming a profile for given aligned sequences.
        by Michael Gribskov [email-masked] (formerly of
        one of the National Labs in the US).
Scrutineer - a protein sequence motif analysis program
You also may want to look into Scrutineer you can get it at:
                        [email-masked]
 
Gribskov, M., McLachlan, A.D. and Eisenberg, D. (1987) Profile
analysis: detection of distantly related proteins. PNAS USA 84,
4355-4358.

Gribskov, M., Methods in Enzymology (1990) 183, PP 146-159
 
URL = http://pscinfo.psc.edu/general/software/cray/c90/profiless/profiless.html
PROFILE-SS is a program that combines the optimal local sequence alignment
algorithm developed by Michael Watterman and Mark Eggert and the Profile
analysis methods of Gribskov into one program that finds the N-best alignments
between a database sequence and a profile. 

You may also want to look at the Protein course that is being worked on
I think they may have links to place to find software for this.
	http://seqnet.dl.ac.uk:8000/vsns-pps/

I have lists of software for 3D prediction and 3D searches also some 
papers on these topics.

What in particular are you trying to study?

For 2D predictions almost any decent Genetics software package  on any
platform does 2D predictions.

Good luck!

Mark
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From: Kaiqi Chen <[email-masked]>

   As far as I know, there is a book: "Prediction of protein 
structure and the principles of protein conformation", edited 
by Gerald D. Fasman.

kaiqi chen
[email-masked]
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From: "J. Mike Sauder" <[email-masked]>

	I'll do a little searching around, but just a quick search yielded a
couple of references you might want to look up.
	The classic reference is Chou and Fasman.  Some simple parameters for
estimating helix or beta sheet formation are termed 'Chou-Fasman parameters'.
I'm not sure which of the following references is most helpful, since I don't
have them handy:

Chou & Fasman (1971) Biochemistry 13:211
Chou & Fasman (1978) Advances in Enzymology 47:45-148

	I also found a reference to a book by Fasman that you might find very
helpful:

Fasman (1989) "Prediction of Protein Structure and Principles of Protein
	Conformation", Plenum, New York.

	Hope this is helpful for a start.  I'll also look around and see if
I can find any places that have algorithms or programs that actually do 
secondary structure prediction.
								-- Mike
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From: Lin Dawei <[email-masked]>

  Secondary prediction has a long history, I think. The most famous one 
is Chou-Fosman methods. You may already know that. It is in fact a 
statistic method. Up to now, there is many method to predict secondary 
structure of protein, like Garner method, neutral network method etc. 
But now the precision of all this methods less than 65% for 
3-states prediction (alpha-helix, beta-sheet, random coil). So secondary 
prediction is realy a tough work to do. Now people also use multiple 
alignment method to improve the precision, but it also seem have a lot 
work to do. TiBS and Current opinions in biology are two very good 
journal to beginners. 
  For the folding problem, which I am also interested in, is not a mature 
field I think. Now, there is no method can predict protein folding just 
according to its primary sequence. But people have already develop many 
excellent methods to know better about it. You can also read the above 
two journals I recommend for recent advantence.

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From: "William T. Winter" <[email-masked]>

look up the published work of Gerald Fasman in particulra Fasman and Chou.

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From: Erich Bauer <[email-masked]>

anyway, it would be fine to know about your background:
there are millions of billions of articels/books etc. on that suject,
but no clear answer to the proteinfolding problem - and sec.str.pred.
is part of this - has been given yet.
basicly there are two approaches: heuristics, such as neural net procedures
with an average accuracy up to 70% ( Rost/Sander) and no-knowledgebased,
very time consuming methods.
if you want, i can point you out some more literature but essentially
people think it works as follow:
after transcription/processing etc. the protein folds 
a) in vivo f.i. protected from agglomeration by chaperons
b) in vitro spontanously from a random coil 
very fast into a molten globe state which has lots of secondary structure.
secondary structure formation is the initial part of folding,
basicly driven by hydrophobic interactions, the molten globe state
contains already a lot of regulariteis ( i.e. sec.str. exactly as the
later natural state does.)
in that sense you may call this a fundamental ( building)
 block, although nothing is decided.
this process is very fast and probably follows a pathway, i.e. a cascade
of well defined yet flxible intermediate states.
from there it takes a time scale of seconds to refold into the native state,
which is the global or a very good local optimum.
there is, however several regions of high and others of binary 
uncertainity, leaving 
the molecule flexible enough to expell water and resort the overall
configuration of such sec.str. elements.
maybe long range interactions, forming in the later stages of folding
are essential for the formation of the final 3D ( i.e. tertiary) structure.
these are the reason ( probably ) why prediction over 70% is tough.

send an email to
[email-masked]
with a cont. like this:

predict secondary structure
 concise result
 #An2_119
 RNKFSKMTDNKW.....

and you will get the answer to our sequence.

open for further questions
erich
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From: Stanley Krystek <[email-masked]>

The area you comment on has been of great concern to many of us who
are chemists, biochemists or computational chemists.  There have been
many empirical and even more more theoretical approaches developed for
generating a set of rules for understanding protein structure and
predicting individual secondary structure elements or tertiary folds.
I have recently written reviews which will be published this year in
the book Current Protocols in Protein Science. We cover the most
common empirical methods for structure prediction.  One good reference
for this work is the book on protein structure prediction written by
Fasman.  The book is titled "Prediction of Protein Structure and
the Principles of Protein Conformation" G. Fasman ed., Plenum Press
1989.

There are many problems in using amino acid sequence alone to predict
protein structure.  For example, protein folding may involve "chaperones"
to help in the folding process.  Therefore, the "rules" derived for
empirical (or statistical) predictions are not a complete description 
of the folding process.  Likewise we have been unable to develop the 
theoretical tools that would allow us to sample the folding of a protein
using molecular dynamics.  Our forcefields still approximate many of the
important forces involved in the formation of protein structure (i.e.
electrostatics and solvations effects).

So the questions you ask are ones for which we strive to answer.
The attempts to describe through empirical and explicit forcefields
protein structure is ongoing in most chemistry, biochemistry, molecular 
biology departments as well as most pharmaceutical companies. 

stan
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From: Bob Funchess <[email-masked]>

   There are many programs designed to do just this sort of thing; for some
examples of predictor algorithms you might try the following papers:

Holley, L.H. and Karplus, M.
   Proc. Natl. Acad. Sci. USA 86, 152-156 (1989) 

Garnier, J.; Oglethorp, D.J.; and Robinson, B.
   J. Mol. Biol. 120, 97-120 (1978) 

Chou, P.Y. and Fasman, G.D.
   Adv. in Enzymology 47, 45-148 (1978) 

  (I happen to have these three references in particular handy because
these methods or derivatives of them are used in the Molecular Simulations
program QUANTA; there are also any number of other methods.)

           Bob Funchess
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From: Stanley Krystek <[email-masked]>

The area you comment on has been of great concern to many of us who
are chemists, biochemists or computational chemists.  There have been
many empirical and even more more theoretical approaches developed for
generating a set of rules for understanding protein structure and
predicting individual secondary structure elements or tertiary folds.
I have recently written reviews which will be published this year in
the book Current Protocols in Protein Science. We cover the most
common empirical methods for structure prediction.  One good reference
for this work is the book on protein structure prediction written by
Fasman.  The book is titled "Prediction of Protein Structure and
the Principles of Protein Conformation" G. Fasman ed., Plenum Press
1989.

There are many problems in using amino acid sequence alone to predict
protein structure.  For example, protein folding may involve "chaperones"
to help in the folding process.  Therefore, the "rules" derived for
empirical (or statistical) predictions are not a complete description 
of the folding process.  Likewise we have been unable to develop the 
theoretical tools that would allow us to sample the folding of a protein
using molecular dynamics.  Our forcefields still approximate many of the
important forces involved in the formation of protein structure (i.e.
electrostatics and solvations effects).

So the questions you ask are ones for which we strive to answer.
The attempts to describe through empirical and explicit forcefields
protein structure is ongoing in most chemistry, biochemistry, molecular 
biology departments as well as most pharmaceutical companies. 

stan
--
 Stan Krystek      
 Bristol-Myers Squibb
 [email-masked] 

>From [email-masked] Feb 17 09:43:16 1995

You should look at publications from the following groups;

MJE Sternberg et al. 
GJB Barton et al.
JM Thornton et al.
TL Blundell et all
W. Taylor et al
Fred Cohen et al.
Zvelebil et al.

And there are many more, who are actively working on solving the 
problem of foldin, prediction and accuracy of prediction of proteins
from sequence.

Marketa Zvelebil
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Date: 10 FEB 1995 18:25:22 GMT 

This is a very active field.  I don't have specific referrences, but if no
expert in this field responds in this newsgroup, I'd suggest cross-posting
to several other newsgroups such as bionet.general, bionet.molec-model (I
think I have the name right) and any with "protein" in the title.  If you 
still have no luck, try Biophys J. or Protein Science.  Good luck.
				Yours,
				Bill Tivol
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