Problem in 3D modelling using SWISS-MODEL

Question

[Yoosef]

Hello I am trying to use SWISS-MODEL to draw 3D model for SDCCAG8 protein. My problem is that resulted templates and models do not cover the entire protein sequence properly and a big part of my protein sequence is not involved in modeling. I have the same problem in modeling with CSF1R protein. Anybody knows the solution for this problem? I will be so pleased if you could share it with me.

[Joe]

You can try ITASSER. It will generate full length models, but just be aware that the less real data involved, the more spurious the structure could be,

Answer 1

[Mensur Dlakic]

SWISS-MODEL does comparative modeling (AKA template modeling). It can model - poorly - a part of your protein that is lacking a template in the middle, but it can't model the portion at either end without a template. Here is a diagram:

SDCCAG8    AAAAAAAHHHHHHGGGGGGGDDDDDDDD
template   AAAAAAA------GGGGGGG--------

SWISS-MODEL will model the HHH portion of your protein because it is anchored at both ends by a matching template, but that HHH section won't be worth much because it is unlikely to be very accurate. The DDD portion of your protein will not be modeled at all since it does not have an anchor at its C-terminus. You can probably force it to model the DDD part, but it will be fairly useless if longer than 10-15 residues. In other words, it is better to have a reliable partial model of your protein than to have a complete model for which parts are very likely to be meaningless.

[Yoosef]

Thanks a lot for your response. I have a novel mutation and i'm trying to use this database to analyze the effect of mutation on protein folding. If SWISS-MODEL has such problem in some proteins, what are other 3D modeling databases which can be used for my purpose?

[Mensur Dlakic]

If the mutation is not covered by available structural templates, no modeling program will be able to create a good 3D model. This is not a deficiency of SWISS-MODEL - it applies to any protein modeling program.

More importantly, 3D modeling is not a good way to assess the effect of mutations on folding, especially of point mutations. Comparative modeling programs by design try to create a model structure that is similar to the template. With very few exceptions, the protein backbone will look the same after single-residue mutations. The energy change in that structure may be a better way to assess the effect of mutations, but you first need a reliable model. That brings us back to the original requirement that a structural template is needed for a good model.

[Joe]

Agreed with the above, with the exception that tools like ITASSER (IIRC), finish the structure simulation with a molecular dynamics energy minimisation step, which allows any constrained geometries or 'unnatural' folds, to relax. If a step like this is incorporated in the tool you use (or you do your own MD step after the fact with the built model) you may be able to find out what effect that mutation has had on the structure.

[Yoosef]

Thanks a lot for your kind response and guidances. It helped a lot. I'm trying to learn molecular dynamic simulation for complete analysis of mutations effect. But still i haven't been able to find good training source like a book or a videos. Are you familiar with any good training source for molecular dynamic simulation specially with GROMACS?

[jgreener]

Are you familiar with any good training source for molecular dynamic simulation specially with GROMACS?

I have found these tutorials useful: http://www.mdtutorials.com/gmx/