Protein-Protein or Protein-Peptide alchemistry?

amin-sagar commented 5 months ago

Dear OpenFE team. Thanks for this awesome work. This is related to https://github.com/OpenFreeEnergy/openfe/issues/633 https://github.com/OpenFreeEnergy/openfe/issues/634 and https://github.com/OpenFreeEnergy/openfe/issues/636 I would like to start with a protein-peptide co-crystal structure and modify the peptide by

1) doing amino acid mutations 2) adding small groups like methyl, acetyl etc.

Are there any special instructions for doing such calculations or should I treat my peptide as a small molecule and follow the lysozyme-benzene tutorial? I would be really grateful for any suggestions. Best, Amin.

IAlibay commented 5 months ago

@amin-sagar, thanks for your question.

Unfortunately at this time, treating an alchemical peptide with an appropriate protein force field is not be feasible. You could treat it as a small molecule but although you would have to stick to either GAFF or OpenFF small molecule force fields and AM1-BCC partial charges (both of which are not very adequate for treating peptides).

amin-sagar commented 5 months ago

Thanks @IAlibay Is there a way to support espaloma? https://github.com/choderalab/espaloma It seems to work well with peptides and openMM. i.e. design the alchemical transformation, parameterize using espaloma and run the simulations? Best, Amin

IAlibay commented 5 months ago

So I think we can use espaloma for the small molecule, so you could have your peptide be parameterized with this and have the protein prepped with whichever AMBER FF version you want.

To do think I think you'd need to set the small molecule forcefield to whichever version of espaloma you want to try out. I haven't tried this out at all though - @mikemhenry might know if there's some issues to be careful of.

amin-sagar commented 2 months ago

Thanks @IAlibay @mikemhenry I tried doing a protein-peptide FEP with a simple W to A mutation which is known to drastically reduce affinity. First I assigned charges using espaloma and used openff-2.1.1 as the small molecule force field. For one of the repetitions, I get some results. forward_reverse_convergence But, for the other repetitions, there doesn't seem to be acceptable convergence mbar_overlap_matrix This is not unexpected as openff is probably not the best force field for peptides. I then tried to use espaloma by setting "small_molecule_forcefield": "espaloma-0.3.2" but I get

Parameterizing molecules
Source 'espaloma-0.3.2.offxml' could not be read. If this is a file, ensure that the path is correct.
Looked in the following paths and found no files named 'espaloma-0.3.2.offxml':
    /mnt/Comp_Chem/Projects/Tests/Test_OpenFE/Test_Bic1/test_espaloma/network_setup/transformations
    /home/amin/mambaforge/envs/openfe_env/lib/python3.11/site-packages/openforcefields/offxml
    /home/amin/mambaforge/envs/openfe_env/lib/python3.11/site-packages/smirnoff99frosst/offxml
    /home/amin/mambaforge/envs/openfe_env/lib/python3.11/site-packages/openff/amber_ff_ports/offxml
If 'espaloma-0.3.2.offxml' is present as a file, ensure it is in a known SMIRNOFF encoding.
Valid formats are: ['XML']
Parsing failed while trying to parse source as a file with the following exception and message:
<class 'openff.toolkit.utils.exceptions.SMIRNOFFParseError'>
syntax error: line 1, column 0

Done with all simulations! Analyzing the results....
Here is the result:
    dG = None ± None

Error: The protocol unit 'Parent to W2A repeat 2 generation 0' failed with the error message:
ValueError: No registered small molecule template generators could load force field 'espaloma-0.3.2'
Available installed force fields are:
  GAFFTemplateGenerator: ['gaff-1.4', 'gaff-1.8', 'gaff-1.81', 'gaff-2.1', 'gaff-2.11']
  SMIRNOFFTemplateGenerator: ['tip3p_fb-1.0.0', 'openff-1.3.0', 'tip5p', 'openff-2.1.1', 'openff-2.2.0-rc1', 'tip4p_ew-1.0.0', 'openff-1.3.1-alpha.1', 'opc3-1.0.1', 'openff-1.2.1', 'spce-1.0.0', 'tip3p_fb', 'openff-2.0.0-rc.1', 'tip3p_fb-1.1.1', 'tip4p_fb-1.0.1', 'tip4p_ew', 'tip3p_fb-1.1.0', 'openff-2.0.0-rc.2', 'tip4p_fb-1.0.0', 'openff-1.0.0-RC1', 'openff-1.0.0-RC2', 'opc', 'openff-1.2.0', 'tip3p-1.0.0', 'tip3p', 'openff-2.0.0', 'openff-1.3.1', 'tip3p-1.0.1', 'openff-1.1.0', 'opc-1.0.0', 'opc-1.0.2', 'openff-1.0.1', 'opc3-1.0.0', 'openff-2.1.0-rc.1', 'tip5p-1.0.0', 'opc3', 'openff-1.1.1', 'opc-1.0.1', 'spce', 'openff-1.0.0', 'openff-2.1.0', 'tip4p_fb', 'smirnoff99Frosst-1.0.9', 'smirnoff99Frosst-1.0.6', 'smirnoff99Frosst-1.0.4', 'smirnoff99Frosst-1.0.0', 'smirnoff99Frosst-1.1.0', 'smirnoff99Frosst-1.0.3', 'smirnoff99Frosst-1.0.7', 'smirnoff99Frosst-1.0.5', 'smirnoff99Frosst-1.0.2', 'smirnoff99Frosst-1.0.8', 'smirnoff99Frosst-1.0.1', 'ff14sb_off_impropers_0.0.2', 'ff14sb_off_impropers_0.0.4', 'ff14sb_off_impropers_0.0.3', 'ff14sb_off_impropers_0.0.1']
  EspalomaTemplateGenerator: ['espaloma-0.2.2']

I also tried espaloma-0.2.2, but I get

Preparing the hybrid topology simulation
Parameterizing molecules
Source 'espaloma-0.2.2.offxml' could not be read. If this is a file, ensure that the path is correct.
Looked in the following paths and found no files named 'espaloma-0.2.2.offxml':
    /mnt/Comp_Chem/Projects/Tests/Test_OpenFE/Test_Bic1/test_espaloma/network_setup/transformations
    /home/amin/mambaforge/envs/openfe_env/lib/python3.11/site-packages/openforcefields/offxml
    /home/amin/mambaforge/envs/openfe_env/lib/python3.11/site-packages/smirnoff99frosst/offxml
    /home/amin/mambaforge/envs/openfe_env/lib/python3.11/site-packages/openff/amber_ff_ports/offxml
If 'espaloma-0.2.2.offxml' is present as a file, ensure it is in a known SMIRNOFF encoding.
Valid formats are: ['XML']
Parsing failed while trying to parse source as a file with the following exception and message:
<class 'openff.toolkit.utils.exceptions.SMIRNOFFParseError'>
syntax error: line 1, column 0

Done with all simulations! Analyzing the results....
Here is the result:
    dG = None ± None

Error: The protocol unit 'Parent to W2A repeat 2 generation 0' failed with the error message:
ValueError: No registered small molecule template generators could load force field 'espaloma-0.2.2'
Available installed force fields are:
  GAFFTemplateGenerator: ['gaff-1.4', 'gaff-1.8', 'gaff-1.81', 'gaff-2.1', 'gaff-2.11']
  SMIRNOFFTemplateGenerator: ['tip3p_fb-1.0.0', 'openff-1.3.0', 'tip5p', 'openff-2.1.1', 'openff-2.2.0-rc1', 'tip4p_ew-1.0.0', 'openff-1.3.1-alpha.1', 'opc3-1.0.1', 'openff-1.2.1', 'spce-1.0.0', 'tip3p_fb', 'openff-2.0.0-rc.1', 'tip3p_fb-1.1.1', 'tip4p_fb-1.0.1', 'tip4p_ew', 'tip3p_fb-1.1.0', 'openff-2.0.0-rc.2', 'tip4p_fb-1.0.0', 'openff-1.0.0-RC1', 'openff-1.0.0-RC2', 'opc', 'openff-1.2.0', 'tip3p-1.0.0', 'tip3p', 'openff-2.0.0', 'openff-1.3.1', 'tip3p-1.0.1', 'openff-1.1.0', 'opc-1.0.0', 'opc-1.0.2', 'openff-1.0.1', 'opc3-1.0.0', 'openff-2.1.0-rc.1', 'tip5p-1.0.0', 'opc3', 'openff-1.1.1', 'opc-1.0.1', 'spce', 'openff-1.0.0', 'openff-2.1.0', 'tip4p_fb', 'smirnoff99Frosst-1.0.9', 'smirnoff99Frosst-1.0.6', 'smirnoff99Frosst-1.0.4', 'smirnoff99Frosst-1.0.0', 'smirnoff99Frosst-1.1.0', 'smirnoff99Frosst-1.0.3', 'smirnoff99Frosst-1.0.7', 'smirnoff99Frosst-1.0.5', 'smirnoff99Frosst-1.0.2', 'smirnoff99Frosst-1.0.8', 'smirnoff99Frosst-1.0.1', 'ff14sb_off_impropers_0.0.2', 'ff14sb_off_impropers_0.0.4', 'ff14sb_off_impropers_0.0.3', 'ff14sb_off_impropers_0.0.1']
  EspalomaTemplateGenerator: ['espaloma-0.2.2']

I couldn't find more details about using espaloma in the documentation. I would be really grateful for any suggestions and happy to run and share protein-peptide FEP benchmarks using espaloma.

OpenFreeEnergy / openfe

Protein-Protein or Protein-Peptide alchemistry? #682