Subject: Re: knowledge based protein modeling

From: [email-masked] (David Mosenkis)
Date: Fri, 17 Mar 1995 18:21:59 GMT

Michelle,

> Is it possible to generate a very crude model for a small protein (95 aa)
> if you know the following:  hydrophobic/hydrophilic regions, antibody
> binding epitopes, carbohydrate linkage sites, and disulfide linkages? 
> If this is possible could you provide me with some references and what
> programs are being used.  I currently have access to most modules for
> sybyl 6.10 which are running on various SGI platforms.  I know that
> homology modeling is possible using "composer", "homology", etc., but in
> this case there are no related or homologous (based 20 % homology
> cut-off).  We don't need an "acurate" model, rather a very crude "first"
> approximation which should provide us with the gross anatomy of the
> protein. 

  Knowledge of the hydrophobic regions, binding sites, and disulfides, by
  itself, will not be sufficient to produce even a rough 3D model.  The
  only hope is if there is a protein of known structure that has a similar
  structure to yours.  How to find if such a protein exists?  Certainly the
  logical first step is to search the database of known structures for any
  with high sequence similarity, as you have done.  In this case, you found
  no matches down to 20% sequence identity.  I have seen a few cases where
  jumbling the alignments can detect a significant sequence relationship
  even with sequence identity as low as the high teens.  So you could try
  lowering your % identity cutoff to 15%, and see if Composer's sequence
  homology search turns up any sequences with a significance score of at
  least 4 (i.e. native alignment score is > 4 standard deviations better
  than jumbled versions of same sequences).

  Another approach to locating a protein with the same fold is to use the
  inverse folding approach, which tries threading a sequence through known
  protein folds, and seeing if any of them accomodates the sequence
  extremely well.  Such methods have been published by a number of groups,
  including those of Eisenberg, Thornton, Crippen, Sippl, and Bryant,
  Johnson, and Skolnick.  I was involved in development of a Tripos product
  called MatchMaker that implements the Skolnick group approach to this
  problem[1,2,3], and includes analysis tools for reliably assessing the
  correctness of a match of your sequence to a known 3D structure.  If a
  strong match is found, the result is just the sort of crude structural
  model of your sequence that you are seeking, that provides the "gross
  anatomy of the protein".  Contact me or Tripos for more information.

Good luck,
David Mosenkis  ([email-masked])
Tripos, Inc.

1.  Godzik, A., Kolinski, A., and Skolnick, J. (1992) "Topology
Fingerprint Approach to the Inverse Protein Folding Problem", J. Mol.
Biol. 227, 227-238.

2.  Gozdik, A. and Skolnick, J.  (1992)  "Sequence-structure matching in
globular proteins:  Application to supersecondary and tertiary structure
determination", Proc. Natl. Acad. Sci., Vol. 89, pp. 12098-12102.

3.  Godzik, A., Kolinski, A., and Skolnick J. (1993) "De novo and inverse
folding predictions of protein structure and dynamics", J. Comp. Aid. Mol.
Design, Vol. 7, pp. 397-438.