Subject: Summary: Large loop+Binding site

From: "Jianhui Wu" <[email-masked]>
Date: Tue, 30 May 2000 11:08:27 -0400

Hi,

Last week, I asked a question about constructing a large loop (55
residues). It seems that it is a mission impossible if there is no
suitable template. I would like to thank Professor Goldblum for his
help. Please find my original question and the respond as follow.

Sincerely,

Jian Hui Wu

*******Original question***************************
To model a large flexible loop in the protein modelling is risky.
However, if the loop is found to involve with ligand binding (it
happens!), then the key step is to get a good model of the loop.
Moreover, the loop conformation usually will change on the binding of
ligand. In my case, the loop contains about 55 residues. What is the
state of the art in modelling this kind of loop? Do you know any
successful case?  I got several models of this large loop, most of them
point away from the protein surface! Any suggestion will be greatly
appreciated.
*********Response*********************************
Dear  Jian Hui Wu,

I am afraid that there can not be a very useful response at this moment
to your question about loop construction, unless there is a way to use
homology modelling and compare your loop sequence to a known structure
to which it is homologous. Your loop size brings it really
to the size of a small protein. Modelling de novo such a long loop
coincides
with protein folding, and no one has yet succeeded in such protein
folding
experiments over about 30-35 residues.

We are at this moment developing a loop prediction algorithm, which
 may be useful for loops of 20-30 residues. This is a huge combinatorial

problem if one wishes to determine all the main chain + side chain
rotamers.
There are some examples of such long loops in proteins, I can remember
now the caspase inhibitor protein which has such a loop (three different

solutions appear on the pdb file) which is, as you imply, close to the
protein's surface. Sorry for not being more useful...

Yours Sincerely,

Amiram Goldblum

Prof. of Medicinal Chemistry
School of Pharmacy

Hebrew University of Jerusalem, Israel 91120

Tel: 972-2-6758701 FAX: 972-2-6410740
email: [email-masked]
*********************************************
E.O.F.