I am working with a trans-membrane protein that I have modeled by homology modelling. In all predicted structures, the trans-membrane part have been modeled nicely. But I face problem with the structure of a long intracellular loop (~ 60 residues). As that part has no similarity with previously solved crystal structure, the loop become disordered. Early reports also suggested partial modelling by removing the intracellular loop part. So kindly suggest some methodology to model the loop region to get the complete structure of that protein.
the results of homology modeling is largely depend on the package you used especially when you have less sequence similarity and identity. It would be good if you take more number of template structure for generating homologue of your query target sequence. import as much as input template on the basis of evolutionary and similarity basis and try to generate the model manually.
However online servers like phyre and swiss port can generate it with good reliability.
You could try ab-initio folding but to be fair, there is no way to prove the result is plausible. It's better to admit defeat and try to get experimental data.
If you have huge number of similar sequences (in thousands) to your loop sequence then probably you can try something like co-evolution analysis using EVFold (http://evfold.org/evfold-web/evfold.do) to guide your modelling. In the parent papers of EVFold, Chris Sander's group has predicted structures of several transmembrane proteins.
Thank you all for your kind suggestions. Athar and Rohit, the ICL portion has no similar structural homolog. To date all similar crystal structures are solved by removing the ICL part due to some stabilization issue.
Being an indel, it would have to be something you can fit as a separate domain onto the surface of the protein. So your approach to do the homology by hacking that section out makes a lot of sense.
The main problem may be the transmembrane part. Is this piece of stuff within the membrane or is it on either side of the membrane? If it is outside the membrane, then try some protein secondary structure prediction to get some idea of what sort of order it might have, and try some of the CASP predictors to see what that separate piece generates. If it is inside the membrane, well ..... hmm..... One way would be to fit the structure as you did with homology, and then lock that in place and find a tentative solution for the hacked out piece by constraining the known part and letting some predictors deal with the rest of it. It is likely to be a very questionable solution. Nevertheless, at least this way, you can specify that the structure of the indel is unknown, but you have plenty of support from homology for the rest of the structure.
That is quite a long indel and almost certainly is at the surface.
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