# Inconsistency in protein-peptide modeling with CHARMM

**URL:** <https://gromacs.bioexcel.eu/t/inconsistency-in-protein-peptide-modeling-with-charmm/2906>\
**Category:** User discussions\
**Created:** [October 4, 2021, 4:41pm UTC](https://gromacs.bioexcel.eu/t/inconsistency-in-protein-peptide-modeling-with-charmm/2906 "2021-10-04T16:41:27Z")\
**Posts on this page:** 6\
**Page:** 1

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**Author:** ![Mirrty](https://avatars.discourse-cdn.com/v4/letter/m/919ad9/32.png) [@Mirrty](https://gromacs.bioexcel.eu/u/Mirrty)\
**Post date:** [October 4, 2021, 4:41pm UTC](https://gromacs.bioexcel.eu/t/inconsistency-in-protein-peptide-modeling-with-charmm/2906/1 "2021-10-04T16:41:27Z")

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GROMACS version: 2021.3  
GROMACS modification: Yes/No

I am trying to do modeling of a small peptide with a protein. I tried two ways of treating the complex:

1. small peptide as a part of a protein
2. small peptide as a ligand

In the first case I don’t have to do preprocessing and I can just start the calculation as for one simple protein. In second case I am obtaining the .itp files for a small peptide from SwissParam and start calculation as a protein-ligand complex.

I expected to see both results to be similar, however every time I treat peptide as a ligand (and not part of a protein) , the peptide immediately looses its secondary structure, got unfolded and produce results far away from crystal structure.

Why there is such a discrepancy and what way of treating peptide is more correct?

Thanks!

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**Author:** ![jalemkul](https://dub1.discourse-cdn.com/flex017/user_avatar/gromacs.bioexcel.eu/jalemkul/32/18_2.png) [@jalemkul](https://gromacs.bioexcel.eu/u/jalemkul)\
**Post date:** [October 4, 2021, 4:52pm UTC](https://gromacs.bioexcel.eu/t/inconsistency-in-protein-peptide-modeling-with-charmm/2906/2 "2021-10-04T16:52:53Z")

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The peptide topology should be generated using the standard protein force field, not SwissParam. The latter is designed for general-purpose ligand topologies and is not highly optimized in the way that the protein force field requires. `pdb2gmx` can generate the entire topology for you.

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**Author:** ![Mirrty](https://avatars.discourse-cdn.com/v4/letter/m/919ad9/32.png) [@Mirrty](https://gromacs.bioexcel.eu/u/Mirrty)\
**Post date:** [October 4, 2021, 5:17pm UTC](https://gromacs.bioexcel.eu/t/inconsistency-in-protein-peptide-modeling-with-charmm/2906/3 "2021-10-04T17:17:05Z")

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@jalemkul, thank you for the explanation! My problem however that I have non-standard peptides with the bridges between some of the residues, so I can not treat them as a part of a protein. Maybe it will help if I increase the penalty in POSRES\_LIGAND file?

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**Author:** ![jalemkul](https://dub1.discourse-cdn.com/flex017/user_avatar/gromacs.bioexcel.eu/jalemkul/32/18_2.png) [@jalemkul](https://gromacs.bioexcel.eu/u/jalemkul)\
**Post date:** [October 4, 2021, 5:28pm UTC](https://gromacs.bioexcel.eu/t/inconsistency-in-protein-peptide-modeling-with-charmm/2906/4 "2021-10-04T17:28:37Z")

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A low quality topology will eventually cause problems. You should parametrize the only nonstandard residues carefully and incorporate them into the protein force field so you can generate a reasonable topology.

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<div class="post-metadata">

**Author:** ![Mirrty](https://avatars.discourse-cdn.com/v4/letter/m/919ad9/32.png) [@Mirrty](https://gromacs.bioexcel.eu/u/Mirrty)\
**Post date:** [October 4, 2021, 6:26pm UTC](https://gromacs.bioexcel.eu/t/inconsistency-in-protein-peptide-modeling-with-charmm/2906/5 "2021-10-04T18:26:48Z")

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@jalemkul , thanks. I have red a brief explanation on how to create a forcefield for a protein with some non-standard residues, but my peptides have a ring system (please, see attached), so what could be the workflow in this case? ![bridgepept](https://europe1.discourse-cdn.com/flex017/uploads/bioexcel1/original/2X/e/ef2c05795fa55e66a6531ad635fb2a4ed714f144.jpeg)

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<div class="post-metadata">

**Author:** ![jalemkul](https://dub1.discourse-cdn.com/flex017/user_avatar/gromacs.bioexcel.eu/jalemkul/32/18_2.png) [@jalemkul](https://gromacs.bioexcel.eu/u/jalemkul)\
**Post date:** [October 5, 2021, 12:56am UTC](https://gromacs.bioexcel.eu/t/inconsistency-in-protein-peptide-modeling-with-charmm/2906/6 "2021-10-05T00:56:55Z")

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Parametrize the individual nonstandard amino acids, and add an entry in `specbond.dat` that specifies how they are bonded, and `pdb2gmx` will create the connection between the two.