Request to add tutorial for building cyclic peptides

[astomer2]

I saw david baker's work on building a large ring from scratch in cell, which made me very interested. I looked at the code provided in their attachment materials. It is obvious that it is not compatible with pyrosetta 4 now. Multiple functions and classes are no longer the same. This caused me great pain when trying to reproduce it. I humbly request you to write a tutorial on how to build a cyclic peptide.

[NooraAz]

can you please attach the video link? or the script they used?

[astomer2]

The literature is "Comprehensive computational design of ordered peptide macrocycles", and the material they provide is http://www.sciencemag.org/content/358/6369/1461/suppl/DC1

[NooraAz]

You can compile Rosetta (not pyRosetta) and run simple_cycpep_predict app. Here is its documentation: https://www.rosettacommons.org/docs/latest/structure_prediction/simple_cycpep_predict

[astomer2]

In fact, I have used this mover, but it cannot meet my expectations. I hope to be flexible enough to design cyclic peptides, including mutating amino acids or modifying the way the peptide forms rings.

[vmullig]

There's no tutorial on designing cyclic peptides with PyRosetta because that's not what we've used for this purpose in the past. The 2017 Hosseinzadeh et al. paper has all of the RosettaScripts scripts used for design in the supplement. These could be translated to PyRosetta if you wanted to undertake the task (it would be a pretty straightforward matter of looking at the PROTOCOLS section of the script, figuring out the linear sequence of movers, filters, and simple metrics applied, and configuring them equivalently in PyRosetta), but simpler is just to use the existing RosettaScripts workflow. In addition to that paper, the workflow is extensively documented in these three book chapters:

Mulligan VK and Hosseinzadeh P. (2022). "Computational Design of Peptide-Based Binders to Therapeutic Targets". Chapter 3 of Approaching the Next Inflection in Peptide Therapeutics: Attaining Cell Permeability and Oral Bioavailability, American Chemical Society. (https://pubs.acs.org/doi/abs/10.1021/bk-2022-1417.ch003)

Mulligan VK. (2022). "Computational methods for peptide macrocycle drug design". Chapter 3 of Peptide therapeutics: fundamentals of design, development, and delivery, Springer. (https://link.springer.com/chapter/10.1007/978-3-031-04544-8_3)

Dodd-o J, Acevedo-Jake AM, Azizogli A-R, Mulligan VK, Kumar VA. (2022). "How to Design Peptides". Chapter in Chemokine-Glycosaminoglycan Interactions: Methods and Protocols, Springer. (https://link.springer.com/protocol/10.1007/978-1-0716-2835-5_15)_

If you e-mail me at vmulligan@flatironinstitute.org, I can send you copies of all of these.

In addition, I encourage you to look at the supplementary information in these papers, which all have more examples of RosettaScripts scripts for peptide design. The New Delhi metallo-β-lactamase 1 paper in particular has an extensive scripts repository, with both the original scripts and modernized versions:

Mulligan VK, Workman S, Sun T, Rettie S, Li X, Worrall LJ, Craven TW, King DT, Hosseinzadeh P, et al. (2021). "Computationally designed peptide macrocycle inhibitors of New Delhi metallo-β-lactamase 1". Proc. Natl. Acad. Sci. USA 118(12):e2012800118. (https://www.pnas.org/doi/abs/10.1073/pnas.2012800118)

Hosseinzadeh P, Watson PR, Craven TW, Li X, Rettie S, Pardo-Avila F, Bera AK, Mulligan VK, et al. (2021). "Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites". Nature Commun. 12(1):3384. (https://www.nature.com/articles/s41467-021-23609-8)

Mulligan VK, Kang CS, Sawaya MR, Rettie S, et al. (2020). "Computational design of mixed chirality peptide macrocycles with internal symmetry". Protein Sci. 29(12):2433-2445. (https://onlinelibrary.wiley.com/doi/abs/10.1002/pro.3974)

Dang B, Wu H, Mulligan VK, Mravic M, Wu Y, Lemmin T, Ford A, Silva D-A, Baker D, DeGrado WF. (2017). "De novo design of covalently constrained mesosize protein scaffolds with unique tertiary structures". Proc. Natl. Acad. Sci. USA. 114(41):10852-10857. (https://www.pnas.org/doi/abs/10.1073/pnas.1710695114)

[astomer2]

I have sent you an email, please check it. In addition, I have also attached the xml and pyrosetta scripts I used to design the cyclic peptide. I sincerely hope you can make some suggestions and comments. If my script is finished I will put it under this question.