[chimerax-users] AlphaFold best_model.pdb could not visually overlap the input sequence using matchmaker

[Tristan Croll]

Hi,

There are two main issues I see here. Regarding the overlay: if you look
closely you'll see that the variable domains of the antibody (the two
domains directly contacting the antigen) actually overlay really well. The
other two domains don't, but that's not particularly unusual - if you
compare lots of experimental antibody structures you'll see that these
naturally "rock" quite a bit relative to the variable domains, so there's
no single "true" conformation here.

The second, bigger, issue: AlphaFold (including its variants like
ColabFold) is *not* suitable for predicting antibody/antigen complexes (or,
for that matter, any complexes where all the components didn't evolve in
the same organism). It relies deeply on the use of multiple sequence
alignments to glean information on the co-evolution of interacting partners
over tens to hundreds of millions of years, and can only correctly make
this analysis when all the sequences involved are present in the genomes of
each individual organism. Antibody/antigen complexes don't meet either of
these criteria, so in almost all cases you can expect its predictions for
the antibody/antigen interface to be rubbish.

Best,
Tristan

On Sun, Mar 26, 2023 at 1:37 PM Cheng Fei Phung via ChimeraX-users <
chimerax-users at cgl.ucsf.edu> wrote:

> Hi,
>
> I am trying do "matchmaker #2 to #1" between colab output ( best_model.pdb
> which is pasted here at http://ix.io/4rRO ) and
> https://www.rcsb.org/structure/7CR5
>
> However, as seen in https://i.imgur.com/gHL8to3.png , there is not really
> much visual overlapping since the structures are not rotated properly to
> match each other.
>
> The log for doing matchmaker command is available here at
> https://i.imgur.com/78h5CLq.png
>
> The colab notebook is also saved as a screenshot here at
> https://i.imgur.com/LSTdyZe.png
>
> Manually doing "turn z 1 270 model #1 center #1" or similar rotations
> commands also do not help.
> Please advise.
>
> Regards,
> Phung Cheng Fei
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