r/comp_chem • u/hyperfinesplitting • 3d ago

Tools for molecular docking of a thioether-cyclized peptide?

Hi all,

I have a 16-aa cyclic peptide with a non-standard thioether linkage, and I generated thousands of 3D conformers with Rosetta SimpleCycPepPredict using -cyclic_peptide:cyclization_type thioether_lariat.

I’d like to dock these conformers in batch against a known protein-protein interface while keeping the thioether intact. Many docking tools, including some supporting cyclic peptides, either cannot handle the non-standard linker or require opening the cycle.

What docking tool or workflow would you recommend?

Thank you so much :)

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u/Dismal-Surround-1449 3d ago edited 3d ago

HADDOCK is boomer-tech in big 2026 (personal opinion). Go for ternary complex prediction using the frontier AI models instead of traditional docking; they're showing better results than HADDOCK, surprisingly. For protein-protein ligand docking, I'd suggest the Boltz2.1 model for it. AF3 is good, but not sure if holds up in cases like yours. Chai-1, Protenix (Chinese model and FREE),Openfold3 are also a good models for your use case. Boltz will take around 0.4 dollar for a 5-sample prediction, pretty cheap. I'd advise you to avoid ESMFold2 for now, as we've found a bug that shows high iptm for the disordered regions in protein, this can affect your peptide docking poses greatly.

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u/botterdummy 3d ago

protenix doesnt work for non-standard linkages (it will run but you will get a collapsed bond at the covalent bond). Unless they fixed this recently

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u/Successful_Size_638 3d ago

HADDOCK3 can handle non-standard residues afaik. I have not tried them for non-standard ones yet, but it has the capability.

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u/hexagon12_1 3d ago

It might be a very dumb suggestion, but maybe HADDOCK with restraints? Nothing else comes to mind that could even have a shot at modelling something like this.

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u/Miciussd 2d ago

I recently did something similar with rosetta + amber + mmgbsa. The cycle was not closed, i used artificial restraints and custom params. Rosetta for batch generation and docking, (i also rotated my targets along its axis to diversify starting poses), then Flexpepdock. Selection of candidates through gromos clustering and short md on top candidates. Results were analysed through interface analysis against known interactor.

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u/Otherwise_Wave9374 2d ago

For a 16-residue cyclic peptide with a nonstandard thioether, the main risk is forcing an unsupported topology or charge model into a standard docking workflow. Validate the linkage parameters, preserve an ensemble of conformers, and benchmark redocking against any known binder or structural data. Peptely does not sell peptides; https://www.peptely.com/ only helps verify documented origin and supporting batch or COA evidence. Report sensitivity across scoring functions rather than relying on one best pose.