Extreme regions of proteins usually appear to be disordered and when modeled they appear as random coils or when checked with Profunc tool they appear to be tight turns (mostly beta turns). In most instances these end regions play a major role in protein-protein interactions. Since they do not exhibit a defined secondary or a 3D structure, is there a way to study interactions involving these regions, especially via molecular docking?
How would that help... It will simply model the disordered region as a loop... Would can one actually perform docking with a loop?
If you want to study and compare the P-P interaction energy with experimentally known one. And as you said that the modeled region play major role in interaction, you can use APBS for calculation of electrostatic binding energy and then compare. You can also use fast contact server (http://structure.pitt.edu/servers/fastcontact/ ) for electrostatic energy calculation. As i think simple docking will not solve your problem.
This is not a trivial task. Flexible docking (not only with side chain flexibility) can not yet be solved in a satisfactory manner. Attempts using molecular dynamics simulations are tedious and do not guaranty success.
@ Georgios that's the precise problem im facing... i performed normal mode analysis as this is a 328 residue protein and a conventional MD would be exhausting in terms of computing hours... but still im having trouble studying the nature of interaction between the disordered region of the protein with its ligand, which in this case is another protein...I'll look into what Parth has suggested... if any further suggestions are there please let me know... and thanks...
Hi Manan,
I think you can generate several models with different conformations of this region. Then, you can perform a protein-protein docking analysis (for example: Cluspro server) using each one of your models against the known interacting protein and evaluate the predicted complexes according to the score provided by the program and consistence with some experimental value or literature. In addition, you should be able to use the predicted complexes for more intensive and accurate analysis.
Best,
Aldo
@Jeremey.. to answer your first question, well there is poor conservation in the loop region..The binding partner is relatively defined but the region of interest is partially disordered in the binding partner itself... And unfortunately i do not have heavy computing power, but i will try your suggestion of using rigid docking..
@Aldo... generating different models for a predominantly looped region will not yield very different structures... moreover, following docking using ClusPro for instance, would the complex with the least score be truely accurate enough for analysis... because in this case the interaction is between extreme C terminal regions of two proteins, which are disordered because of which there is not structural details of the interaction available..
As Georgios said this is a difficult task. Your best bet would be to conduct MD simulations with and without ligand. Then compare the stability of those regions.
May I suggest, you can use the following server (structure is not necessary, although it's based on super-secondary structures).
http://sbi.imim.es/iLoops.php
The principles on this approach require the formation of secondary structures (not peptides). We have used it to see the implication of an extreme alfa-helix in Ct, but I don't know if your tail can be structured.
See details in:
http://www.ncbi.nlm.nih.gov/pubmed/23842807
http://www.ncbi.nlm.nih.gov/pubmed/23353828
thank you for the server URL and those for the reference articles
a "loop" is also a term used in Feed forward loop FFL to activate a protein signal
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