<p>Similar to @pippo1980 comment: start with a related standard amino acid, fold it however you are doing that, and then mutate to the nonstandard in the folded structure. You can do this with a toolkit like <a href="https://github.com/openmm/pdbfixer/blob/master/pdbfixer/pdbfixer.py#L729" rel="nofollow noreferrer">pdbfixer</a> for standard AAs, you might need to do <a href="https://stackoverflow.com/questions/47631064/create-a-polymer-chain-of-nonstandard-residues-from-a-single-residue-pdb">something like this</a> to directly add the atoms for nonstandards, using an example pdb structure of the nonstandard AA.</p>
<p>You would then need to follow that with a round of energy minimization in the structure to resolve any large problems in the structure, using a toolkit like <a href="http://docs.openmm.org/7.5.0/api-python/generated/simtk.openmm.openmm.LocalEnergyMinimizer.html" rel="nofollow noreferrer">OpenMM</a>.</p>
<p>If <code>X</code> truly means that you have no idea what's there, then... that's harder. In this specific case lysine may be a best bet, but it may be hard to generalize between e.g. methyllysine, phosphotyrosine, phosphoserine, etc. They're pretty different structurally, so having a good idea of what family of residue you would expect would be helpful.</p>
<p>The safest thing to do would be to go back to the transcript and in vitro translate to get an idea of what that X is. Though that's getting a little complicated compared to just replacing it with a leucine or whatever.</p>

CC BY-SA 4.0
2024-02-01T18:24:52.263Z
2024-02-01T18:24:52.263Z
Maximilian Press
<p>We are working with a large dataset of proteins for folding/docking tests across various tools (AlphaFold, ESM2, RoseTTAFold). In some of the FASTA files, there is an X for a non-standard residue. An example of this is in the 6SEN_1 FASTA file below. Is there a standard method of dealing with these non-standard residues prior to analysis to minimize impact on the folding/docking results?</p>
<pre><code>&gt;6SEN_1|Chains A, B|Transcriptional enhancer factor TEF-3|Homo sapiens (9606)
GPRSVASSKLWMLEFSAFLEQQQDPDTYNKHLFVHIGQSSPSYSDPYLEAVDIRQIYDKFPEKKGGLKDLFERGPSNAFFLVKFWADLNTNIEDEGSSFYGVSSQYESPENMIITCSTKVCSFGKQVVE**X**VETEYARYENGHYSYRIHRSPLCEYMINFIHKLKHLPEKYMMNSVLENFTILQVVTNRDTQETLLCIAYVFEVSASEHGAQHHIYRLVKE
</code></pre>

CC BY-SA 4.0
2024-01-17T18:29:20.280Z
X  Any - Uncommon or Unspecified
pippo1980
CC BY-SA 4.0
2024-01-17T21:49:41.763Z
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8942982/   ---> The role of lysine palmitoylation/myristoylation in the function of the TEAD transcription factors , Just change it to a LYS ??'
pippo1980
<fasta>
Dealing with X Residues in FASTA files prior to folding analysis
# Dealing with X Residues in FASTA files prior to folding analysis

(Asked by: username_0 on 2024-01-17)

We are working with a large dataset of proteins for folding/docking tests across various tools (AlphaFold, ESM2, RoseTTAFold). In some of the FASTA files, there is an X for a non-standard residue. An example of this is in the 6SEN_1 FASTA file below. Is there a standard method of dealing with these non-standard residues prior to analysis to minimize impact on the folding/docking results?
>6SEN_1|Chains A, B|Transcriptional enhancer factor TEF-3|Homo sapiens (9606)
GPRSVASSKLWMLEFSAFLEQQQDPDTYNKHLFVHIGQSSPSYSDPYLEAVDIRQIYDKFPEKKGGLKDLFERGPSNAFFLVKFWADLNTNIEDEGSSFYGVSSQYESPENMIITCSTKVCSFGKQVVE**X**VETEYARYENGHYSYRIHRSPLCEYMINFIHKLKHLPEKYMMNSVLENFTILQVVTNRDTQETLLCIAYVFEVSASEHGAQHHIYRLVKE

**Tags:** fasta
> **Comments:**
> **username_1**: X  Any - Uncommon or Unspecified  
> **username_1**: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8942982/   ---> The role of lysine palmitoylation/myristoylation in the function of the TEAD transcription factors , Just change it to a LYS ??'  

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## 1 answers

### Answer by username_2 on 2024-02-01. Score: 1

Similar to @pippo1980 comment: start with a related standard amino acid, fold it however you are doing that, and then mutate to the nonstandard in the folded structure. You can do this with a toolkit like [pdbfixer](https://github.com/openmm/pdbfixer/blob/master/pdbfixer/pdbfixer.py#L729) for standard AAs, you might need to do [something like this](https://stackoverflow.com/questions/47631064/create-a-polymer-chain-of-nonstandard-residues-from-a-single-residue-pdb) to directly add the atoms for nonstandards, using an example pdb structure of the nonstandard AA.

You would then need to follow that with a round of energy minimization in the structure to resolve any large problems in the structure, using a toolkit like [OpenMM](http://docs.openmm.org/7.5.0/api-python/generated/simtk.openmm.openmm.LocalEnergyMinimizer.html).

If `X` truly means that you have no idea what's there, then... that's harder. In this specific case lysine may be a best bet, but it may be hard to generalize between e.g. methyllysine, phosphotyrosine, phosphoserine, etc. They're pretty different structurally, so having a good idea of what family of residue you would expect would be helpful.

The safest thing to do would be to go back to the transcript and in vitro translate to get an idea of what that X is. Though that's getting a little complicated compared to just replacing it with a leucine or whatever.


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