The error in the simulated annealing stage of the docking

HADDOCK
1

Dear HADDOCK Support Team,

I am currently performing protein–peptide docking using HADDOCK, specifically focusing on kinase molecules as receptors and their corresponding substrate peptides (centered around phosphorylation sites) as ligands. I have encountered recurring unexplained errors that prevent successful job completion, and I would appreciate your assistance in identifying potential causes.

For job ID 530955, the docking run fails during the simulated annealing stage. I have checked the corresponding .log and .out files but could not determine the specific reason for the failure.

For job ID 530911, the run fails during the water refinement stage, again without a clear explanation in the output files.

Interestingly, another job (530857) with similar settings completed successfully. While the protein and peptide structures differ across the jobs, the docking parameters, including the use of explicit distance restraints, were kept the same.

All of these jobs involved:

  • A kinase protein used as the receptor,

  • A peptide segment around a known phosphorylation site as the ligand,

  • A custom .tbl file specifying an explicit distance restraint between the O atom of an Asp residue in the protein and the H atom of a Tyr residue in the peptide.

If you could provide any insight into possible causes of these failures, I would be very grateful. Also, please let me know if there are any specific input or output files you would like me to share for further diagnosis.

Thank you very much for your support.

2

Failures are often related to problems in the input models, e.g. clashes that cause the MD refinement stages to fail.

Try refining your input model before giving those to HADDOCK

3

Thank you so much for your advice.After several trials, I found that the issue seems to lie in the input structure of the peptide used as the ligand.

I would like to ask an additional question.

I have an input model that allows the docking to proceed successfully. However, upon inspecting the resulting complex structure, I noticed that—even though all residues of the peptide were defined as fully flexible—the backbone conformation of the peptide remains almost unchanged from the input structure.

I would like to allow more flexibility in the peptide molecule during the docking calculation. Could you kindly suggest any recommended settings or strategies to achieve this?

Thank you again for your continued support.

4

The amount of conformational changes possible is limited by the rather short protocol (even if for peptide docking the number of refinement steps is extended by a factor four on the server).

Best strategy is to try to sample conformations prior to docking and provide an ensemble of conformations as starting point

5

Hi there,

You can find some good information on our Best Practice Guide for peptides ( Peptide docking – Bonvin Lab )

Almost remained unchained does not mean did not move. Sometimes if the conformation is already good enough, there is no need of conformational changes.

6

Thank you for your quick reply.

I’ll refer to the best practice guide and prepare an ensemble of conformations before docking to try the suggested approaches.