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I am using homology modelling to assign the 3D structure of Torpedo acetylcholine receptor (Unwin 2004, 2bg9 in RCSB) to human muscle nAChR. The problem is, both Torpedo receptor, and human receptor have subunit structure A-B-D-A-E: so a same subunit (A) occurs in the model twice. This seems to cause problems for homology modelling software, as it tends to align the second 'A' sequence over the first 'A' sequence, creating a hole in the pentamer, and not filling it up. Any ideas on how to make sure the modelling software acknowledges the quaternary structure? Below please find a link to a file generated using pdb.gz structure data from Unwin model + a set of corresponding FASTA sequences, and attached picture shows the problem (revealed when alignment is set as shown in the picture, by clicking on the same 'boxes' as in the image). Long story short, I need to get the A subunit to complete the alignment in a different spot than it is automatically placed in, as it occurs in the whole structure twice.

https://swissmodel.expasy.org/interactive/JJ5mQf/models/

image of protein

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  • $\begingroup$ I don't know a proper solution to this, but maybe you could try 'hack' it by changing a few amino acids in one of the two A chains? $\endgroup$ – Nicolai Sep 21 '18 at 12:41
  • $\begingroup$ Thanks for response: was thinking about it, but as I am planning to use it for docking studies with cell-membrane permeating ligand (so can bind both inside and outside): the original Unwin model is quite shabby on its own, homology modelling isn't really optimal either, and docking is notoriously unreliable, so can't quite see how I could justify this 'hacking' (and thus adding another source of unreliability) in a paper. Furthermore, it seems like a type of problem with relatively simple solution: surely, someone must have thought of this before! $\endgroup$ – Jericho Jones Sep 21 '18 at 14:02
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For anyone who will struggle with this problem in the future: The trick is in reading WHOLE of the manual, NOT submitting the whole sequence/badly segmented sequence, and in NOT attempting to input the same subunit twice. It is necessary to upload subunit FASTAs separately as a hetero target, and each subunit ONLY ONCE (so A,B,D,E for A-B-D-A-E receptor), and then search for templates: most probably there is a template with your quaternary structure uploaded somewhere already, and if not, you can choose preferred arrangement afterwards.

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