Hello,
I'm modeling protein structure by Modeller. My template has 66% identity and 99% coverage, however it is in the open state without ligand. For the further analysis closed state of the enzyme is required. I know which of the protein domain should move relating to the rest of the structure. I found homology structures with closed lid, but with only 38% sequence identity. Is there any way to generate this structure in the closed state? Is it a good step to further analysis?
There is a web server at Indian Institute of Technology, New Delhi, called Super Computing Facility for Bioinformatics & Computational Biology. The tool is Bhageerath-H. This may help u as it is a hybrid tool ( Homology as well as fragment based) for protein modeling.
Tomasz Molcan: First of all, I would like to thank you for raising this question. This is one of the problems which could not be solved using straight forward approach of homology modeling.
The problem you have demonstrated popularly called the problem of "kinetic trapping", where the protein is stabilized in a local minima and to attain other conformation you have to take it out of that.
There are different approaches which would help you to do that. You could use one of the following methods to solve it.
A) CONCORD: This method is used to plan and develop protein conformations of an experimentally solved structure based on geometric restraints.
http://www3.mpibpc.mpg.de/groups/de_groot/concoord/
B) Tee-reX: Temperature-enhanced essential subspace replica exchange
(attached publication would help you getting idea about this.
Hope this would serve your purpose. Please feel free to ask questions if you have any queries.
Hi,
U can also try a straight forward option , Normal Mode analysis of Low frequency modes. See confrontational vibrations and select a mode on the basis of the biology of the protein or its close homologue , and use it as a template , re model the structure. May work , best of luck.
I agree with Saugata Hazra, especially about CONCORD.
I also strongly advocate studying this website: http://fizz.cmp.uea.ac.uk/dyndom/
it is full of examples of what you are talking about.
Check out this paper too: Bywater RP. (2013) Protein folding: a problem with multiple solutions. J Biomol Struct Dyn 31(4) 351-362. doi:10.1080/07391102.2012.703062
Is that Opening and closing of protein is depend upon binding of ligand molecule?
If that is the case then, you can model only open state and simulate it than dock it with ligand and simulate further then you will get closed state.
If that is not the case it means without ligand your protein molecule itself exist in two form "open and closed state" and if you want to model closed state that than check in crystal structure paper somewhere it will be mention. Check how many rotational translation moves are required for closed state from open state or check it in pdb file Remark 290/ 350. In short use pymol or vmd software you can used to generate the two form.
I hope it will work for you.
If you are doing ligand docking studies using MD you need to compare:
1 )closed structure with ligand bound
with
2) open structure with ligand "somewhere else".
You need to have ligand present (but "somewhere else") in case 2, otherwise you cannot compare free energies. Whether you work under NVT or NPT conditions, N (number of atoms) MUST be kept constant.
I think that it would be indicated to compute energy interaction between open protein
and ligand. Procedures of molecular mechanics or QM/MM would be used, for example.
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