Subject: RE: CCL:FW: calculate accessible surface area for an occluded cavity

From: "Axel Mathieu" <AMathieu-.at.-tranzyme.com>
Date: Fri, 9 Apr 2004 10:09:27 -0400

James,
 
Success? Well I only studied one protein (human StAR protein) during my studies and have not really used STC in its original form since. According to Pierre Lavigne's paper (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10716177> &db=pubmed&dopt=Abstract&list_uids=10716177) STC performed extremely well as compared to the experimental X-ray data. 
 
In our case for StAR, we were not looking to virtually high-throughput dock small ligands into to the cavity and thus it becomes easy to modify what we need to make STC recognize the ligand. Actually, STC worked fine for cholesterol so long as we changed the "atom names" of the ligands in the pdb file to match those found in proteins (ie: an ordinary carbon was named CA to CM - the other atoms in cholesterol were fine - it is OK if you repeat the same name if you do not have enough to CM so long as you can recognize them if you need to). This was the only modification to our ligand files that we had to do. Although, you clearly need a TER line in your pdb files to indicate where the protein stops and where the ligand starts ...
 
I would try this simple change on a few ligands to see if it works. As I'm certain you realize, STC is only good for large systems where significant changes in SAS are observed/hypothesized. Now that I'm working with small molecules, I only use STC when I study the small molecules alongside proteins ...
 
Since, I've docked some ligands into a protein with a solvent accessible site using part of STC as a part of a multi-factorial scoring method that I implemented in MOE - I found that there was a nice correlation between dH and a good binding pose for our test systems. Success? It worked beautifully for 2 known X-ray test sets resembling our target (the best pose of the ligand, a pentapeptide in this case, was No 1 and was within 1 Ang of the crystal!), BUT we did not perform the biological assays for our target yet ...
 
My understanding is that STC is starting to be used more and more for vHTS so people must have solved the non-protein ligand issue but I have not crossed any papers for this yet.
 
Are you docking in a solvent accessible site or in a cavity?
 
I hope this helps, best regards,
 
APM
 
------------------------------------
Axel Mathieu, Ph.D.
Scientist/Molecular Modeling
Tranzyme Pharma Inc. 
 
Tel:   (819) 820-6840
Fax : (819) 820 6841 
www.tranzymepharma.com
 
NOTICE: This e-mail contains confidential information and is intended for the exclusive use of the addressee. Any other person is strictly prohibited from disclosing, distributing or reproducing it. If you have received this e-mail by mistake, please notify us immediately by telephone or e-mail and delete all copies.
-----Original Message-----
From: james.metz-.at.-abbott.com [mailto:james.metz-.at.-abbott.com] 
Sent: 8 avril, 2004 18:41
To: Axel Mathieu
Cc: james.metz-.at.-abbott.com
Subject: Re: CCL:FW: calculate accessible surface area for an occluded cavity

Axel, 

        Have you any success using STC to predict the binding free energy of small molecules to proteins or 
receptors? 

        I have tried to do this, but the program seems to be highly parameterized to deal only with peptides 
and proteins.  I could never seem to get small molecules to work properly. 

        Regards, 
        Jim Metz 

James T. Metz, Ph.D.
Research Investigator Chemist

GPRD R46Y AP10-2
Abbott Laboratories
100 Abbott Park Road
Abbott Park, IL  60064-6100
U.S.A.

Office (847) 936 - 0441
FAX    (847) 935 - 0548

james.metz-.at.-abbott.com

This communication may contain information that is legally privileged, confidential, or exempt from disclosure.  If you are not the intended recipient, please note that any dissemination, distribution, use, or copying of this communication is strictly prohibited.  Anyone who receives this message in error should notify the sender immediately by telephone or return email and delete it from his or her computer. 

"Axel Mathieu" <AMathieu-.at.-tranzyme.com> 
Sent by: "Computational Chemistry List" <chemistry-request-.at.-ccl.net> 
04/08/2004 02:04 PM 
        
        To:        "CCL" <chemistry-.at.-ccl.net> 
        cc:         
        Subject:        CCL:FW: calculate accessible surface area for an occluded cavity

Qin, 
  
Take a look at the freeware STC (Structure-based thermodynamic calculations -  these are based on SAS) developped by the PENCE/CIHR group in Canada  <http://www.pence.ca/software/stc/html-4.3/stc.html> http://www.pence.ca/software/stc/html-4.3/stc.html. I used STC to propose a cholesterol transfer mechanism for the StAR protein (it conatins a cavity!). In case you're interested, my you'll find my paper abstract and reference at:  <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12459035> http://www.ncbi>.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12459035 
  
STC can quickly report the SAS for each heavy atom of a residue and you just have to add them up, or fill the cavity with the ligand and calculate the difference (supposing your ligand fills the cavity) ... 
  
APM 

-----Original Message-----
From: Q [mailto:qzou-.at.-iupui.edu] 
Sent: 7 avril, 2004 20:30
To: chemistry-.at.-ccl.net
Subject: CCL:calculate accessible surface area for an occluded cavity 
  
Dear All, 
 I have a protein with an internal cavity that has no access to the outside solvent. I would like to calculate the accessible surface area of the residues inside the cavity to see how accessible they are to the cavity. How can I do this or what programs could help to do it? How about NACCESS? Thanks for any input. 
  
Qin