Hi Ryssa, I'm not sure if AlphaFold multimer will run on protein in complex with a 7-9 amino acid peptide because it does a deep sequence alignment for each of the sequences and the peptide sequence is probably too short and AlphaFold may reject it. You can just try it and see if it makes a prediction or gives an error. If it makes a prediction then yes it is trying to produce energetically favorable binding. I've seen it succeed docking a signal peptide to a protein as shown here https://www.rbvi.ucsf.edu/chimerax/data/alphafold-contacts-jun2022/afcontact... and that page tells you how you can see if AlphaFold has high or low confidence in the predicted binding. I think your case is not likely to work unless the peptide is actually part of a bigger protein and you give AlphaFold that full protein sequence. The reason is that AlphaFold looks at evolutionary patterns in the sequences by making a deep sequence alignment often containing thousands of related sequences. But a 7-9 amino acid peptide is too short to get evolutionary information by alignment to all known protein sequences. Still there is some small chance of it working because AlphaFold also has learned about plausible binding even when it does not have sequence evolution info. You cannot specify where to try to bind the peptide with AlphaFold. It will make 5 predictions and you can load the 5 models (ChimeraX will only open the best scoring one by default) and see if it puts the peptide in the same or different locations. The 5 models are the .pdb files in directory ~/Downloads/ChimeraX/AlphaFold/prediction_N. Alphafold cannot use the known structure of your protein, so each prediction has to rerun the full protein and peptide if you want to try different peptides. As Elaine said looking for docking software that can handle peptide ligands may be a better approach. But it is easy to try the AlphaFold approach and see if it produces anything useful. Tom
On Dec 20, 2023, at 10:06 AM, Parks, Ryssa via ChimeraX-users <chimerax-users@cgl.ucsf.edu> wrote:
Hello, I work in a lab that researches biopesticides in the form of insect neuropeptides, which bind to receptor proteins. I am trying to use ChimeraX to model potential binding sites between peptide ligands and their corresponding receptor. Does ChimeraX have this capability? When I was trying to figure this out myself online through the ChimeraX Youtube tutorials and tutorials on the UCSF site, I came across a comment on a video that mentioned I could upload the sequences of my receptor and peptide ligand separated by a comma, and model it as a protein complex, and then I can get information on where the two molecules interact. I’m relatively new to protein research, and so I hadn’t yet thought of ligand-protein interactions as a type of protein complex. My specific questions are:
· When modeling a peptide ligand and a receptor as a protein complex, will ChimeraX accurately predict the relationship between the two molecules based on binding compatibility? Or is it based on something else, like similarity of sequence alignments…? · If multiple binding sites are possible, is there any way to view the different options for multiple binding sites? Or is there any way to restrict the area on the receptor to which my target peptide ligand is predicted to bind (i.e. the extracellular region only)? · The peptide ligands are only 7-9 amino acids in length and do not take very long to model, but the receptor is about 600 amino acids and takes a much longer time to model. Do I have to model protein complexes by re-modeling everything for each different receptor-ligand combination, or can I combine existing models somehow?
I hope these questions aren’t too troublesome, and I hope I haven’t grossly misunderstood ChimeraX’s capabilities.
Thank you for your time,
Ryssa Parks
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