Skip to content

Created swapping example #104

New issue

Have a question about this project? Sign up for a free GitHub account to open an issue and contact its maintainers and the community.

Sign up for GitHub

By clicking “Sign up for GitHub”, you agree to our terms of service and privacy statement. We’ll occasionally send you account related emails.

Already on GitHub? Sign in to your account

Open
wants to merge 9 commits into
base: master
Choose a base branch
from
Open

Created swapping example #104

Show file tree
Hide file tree
Changes from 8 commits
Commits
Show all changes
9 commits
Select commit Hold shift + click to select a range
afdbb95
Modified ATM system preparation for receptor swapping, can include tw…
Feb 6, 2025
b6d7d56
Fixed print of atom indices of ligand 1 and ligand 2
Feb 6, 2025
74f69c8
created swapping calculation of TYK2-JAK2 in examples/
Apr 4, 2025
8862453
Merge branch 'Gallicchio-Lab:master' into master
solmazimi Apr 8, 2025
8f5410a
Removed binary files
Apr 8, 2025
11eda1d
updated .gitignore
Apr 8, 2025
f6ef293
fixed minor changes to swapping example
Apr 9, 2025
7cd2f25
added README.md
Jun 4, 2025
1275fdb
Addressed a few more MR comments
Sep 25, 2025
File filter

Filter by extension

Filter by extension
Conversations
Failed to load comments.
Loading
Jump to
Jump to file
Failed to load files.
Loading
Diff view
Diff view
2 changes: 2 additions & 0 deletions .gitignore
View file
Open in desktop
Copy link
Collaborator

@egallicc egallicc Apr 8, 2025

Choose a reason for hiding this comment

The reason will be displayed to describe this comment to others. Learn more.

Please remove .gitignore

Original file line number Diff line number Diff line change
@@ -0,0 +1,2 @@
*.DS_Store
*.pyc
2 changes: 1 addition & 1 deletion examples/RBFE/cdk2/README.md
View file
Open in desktop
Original file line number Diff line number Diff line change
Expand Up @@ -29,7 +29,7 @@ After the setup script completes, go to the `complexes` directory to run minimiz

For example:
```
cd $HOME/examples/RBFE/cdk2/complexes
cd $HOME/AToM-OpenMM/examples/RBFE/cdk2/complexes
for i in cdk2-* ; do ( cd $i ; bash ./run.sh ) ; done
```
The `run.sh` shell scripts are formatted for optionally running them on a slurm queuing system, such as the one on the Expanse supercomputer. Edit run_template.sh in `$HOME/AToM-OpenMM/examples/RBFE/cdk2/scripts` to adapt them to your cluster.
Expand Down
49 changes: 49 additions & 0 deletions examples/RSFE/TYK2-JAK2/README.md
View file
Open in desktop
Original file line number Diff line number Diff line change
@@ -0,0 +1,49 @@
Relative Binding Selectivity Free Energy of a pair of ligands to TYK2 and JAK2
------------------------------------------------------------------------------

In this example, a swapping calculation will be performed to calculate the relative binding selectivity free energy between a pair of ligands to the isoforms TYK2 and JAK2 of the JAK tyrosine kinase family (Liang et al. (2013): Lead identification of novel and selective TYK2 inhibitors, https://pubmed.ncbi.nlm.nih.gov/23867602/). This example uses an automated workflow to prepare and run the calculation.


### System preparation

Assuming AToM-OpenMM is available under `$HOME/AToM-OpenMM`. Input the pathname that goes to the AToM-OpenMM installation folder in `scripts/setup-settings.sh`. The setup script `setup-atm.sh` reads parameters for the system from the `scripts/setup-settings.sh` file.

```
cd $HOME/AToM-OpenMM/examples/RSFE/TYK2-JAK2
bash ./scripts/setup-atm.sh
```

The setup scripts uses OpenMM and `openmmforcefields` to prepare the ligands and receptors. For the ligands, the OpenFF-2.0.0 force field is used and for the receptors, the protein Amber14 forcefield. The system is solvated in a box. `setup-settings.sh` includes the ligand pairs and their reference alignment atoms. For swapping, alignment atoms are not required, however they are necessary inputs for the workflow. If RBFE calculations are sought to compliment swapping calculations, the alignment atoms selected in this example are sound. Additional ligands can be included and their details must be inputted in this script to automatically set up additional systems.

The displacement vector is necessary for swapping. A sufficiently large displacement must be selected to ensure at least three layers of water molecules between the two proteins. The setup script assumes that the `sdf` files of the ligand are stored in the `ligands` subdirectory and the `pdb` file of the receptor is stored in the `receptor` subdirectory. It is assumed that the pdb file of the receptor is fully prepared with hydrogen atoms etc. The ligands are assumed to have been docked into the binding site.

The setup creates simulation folders in the `complexes` subdirectory for each swapping calculation. For example, `TYK2-JAK2-c41-c46` corresponds to the swapping of c41 from TYK2 to JAK2 and the subsequent swap of c46 from JAK2 to TYK2.

### Minimization and Alchemical Replica Exchange

After setting up the simulation folders, enter the `complexes` subdirectory to run minimization and equilibration for each system. These processes prepare the systems at the alchemical intermediate state at λ=1/2 and the resulting configurations are inputs for alchemical replica exchange simulations. Then alchemical replica exchange can be conducted for each system.

```
cd $HOME/AToM-OpenMM/examples/RSFE/TYK2-JAK2/complexes
for i in TYK2-JAK2-* ; do ( cd $i ; bash ./run.sh ) ; done
```

The `run.sh` shell scripts are formatted for a slurm queuing system. Edit run_template.sh in `$HOME/AToM-OpenMM/examples/RSFE/TYK2-JAK2/scripts` to adapt them to the cluster of choice.

Each simulation is set to run for 24 hours on 1 GPU. Swapping calculations often require longer run times to reach convergence. More GPUs can be deployed by editing the `run_template.sh` file.


### Free Energy Analysis

The relative binding selectivity free energy between the ligand pair A and B are collected by the `free_energies.sh` script in the complexes directory:
```
cd $HOME/AToM-OpenMM/examples/RSFE/TYK2-JAK2/complexes
bash ./free_energies.sh
```

The `free_energies.sh` script produces the swapping free energy estimate and the statistical uncertainty associated with it. In addition, it will indicate if there are large gaps in the distributions of the binding free energies, which would indicate the calculation has not converged. A plot of the distributions, as well as the free energy profile, are also produced for further analysis.

Edit the `free_energies.sh` script to change the number of samples discarded. It is customary to discard the first half of total samples.

If it throws an error named `./analyze.sh: line 34: R: command not found`, please install `r-base` and `UWHAM R package` as follow [installation instructions](https://github.com/Gallicchio-Lab/AToM-OpenMM#installation--usage).

95 changes: 95 additions & 0 deletions examples/RSFE/TYK2-JAK2/ligands/c23.sdf
View file
Open in desktop
Original file line number Diff line number Diff line change
@@ -0,0 +1,95 @@
2_cpd23
3D
Schrodinger Suite 2024-2.
36 38 0 0 1 0 999 V2000
12.9662 -13.2840 19.4792 C 0 0 0 0 0 0
12.8517 -13.2039 18.4083 H 0 0 0 0 0 0
12.0518 -12.6665 20.3254 C 0 0 0 0 0 0
11.2284 -12.1050 19.9092 H 0 0 0 0 0 0
12.1926 -12.7685 21.7046 C 0 0 0 0 0 0
13.2581 -13.5062 22.2527 C 0 0 0 0 0 0
14.1854 -14.1175 21.3880 C 0 0 0 0 0 0
14.0270 -14.0040 20.0131 C 0 0 0 0 0 0
14.7359 -14.4806 19.3523 H 0 0 0 0 0 0
15.5274 -15.0135 22.0354 Cl 0 0 0 0 0 0
13.4380 -13.6641 23.7140 C 0 0 0 0 0 0
13.1246 -14.7222 24.2329 O 0 0 0 0 0 0
13.9831 -12.6422 24.4020 N 0 0 0 0 0 0
14.1827 -11.8121 23.8624 H 0 0 0 0 0 0
14.3110 -12.5710 25.7589 C 0 0 0 0 0 0
14.3822 -13.6594 26.6495 C 0 0 0 0 0 0
14.0957 -14.6499 26.3282 H 0 0 0 0 0 0
14.8266 -13.4403 27.9489 C 0 0 0 0 0 0
14.8910 -14.2706 28.6365 H 0 0 0 0 0 0
15.1737 -12.2228 28.3570 N 0 0 0 0 0 0
15.1150 -11.1624 27.5535 C 0 0 0 0 0 0
14.7296 -11.3277 26.2224 C 0 0 0 0 0 0
14.7565 -10.4849 25.5476 H 0 0 0 0 0 0
15.5526 -9.9201 28.0258 N 0 0 0 0 0 0
16.2255 -9.9359 28.7789 H 0 0 0 0 0 0
15.1697 -8.6947 27.5802 C 0 0 0 0 0 0
14.3549 -8.5371 26.6868 O 0 0 0 0 0 0
15.8270 -7.5062 28.2357 C 0 0 1 0 0 0
15.7798 -6.1409 27.5412 C 0 0 0 0 0 0
15.2894 -6.0378 26.5732 H 0 0 0 0 0 0
16.6433 -5.4771 27.5836 H 0 0 0 0 0 0
14.9469 -6.3943 28.7980 C 0 0 1 0 0 0
13.5685 -6.5374 28.6432 F 0 0 0 0 0 0
11.0626 -11.9588 22.7329 Cl 0 0 0 0 0 0
16.7330 -7.7519 28.7790 H 0 0 0 0 0 0
15.2715 -5.9039 29.7136 H 0 0 0 0 0 0
1 2 1 0 0 0
1 3 1 0 0 0
1 8 2 0 0 0
3 4 1 0 0 0
3 5 2 0 0 0
5 6 1 0 0 0
5 34 1 0 0 0
6 7 2 0 0 0
6 11 1 0 0 0
7 8 1 0 0 0
7 10 1 0 0 0
8 9 1 0 0 0
11 12 2 0 0 0
11 13 1 0 0 0
13 14 1 0 0 0
13 15 1 0 0 0
15 16 1 0 0 0
15 22 2 0 0 0
16 17 1 0 0 0
16 18 2 0 0 0
18 19 1 0 0 0
18 20 1 0 0 0
20 21 2 0 0 0
21 22 1 0 0 0
21 24 1 0 0 0
22 23 1 0 0 0
24 25 1 0 0 0
24 26 1 0 0 0
26 27 2 0 0 0
26 28 1 0 0 0
28 29 1 0 0 0
28 32 1 0 0 0
28 35 1 0 0 0
29 30 1 0 0 0
29 31 1 0 0 0
29 32 1 0 0 0
32 33 1 0 0 0
32 36 1 0 0 0
M END
> <i_m_Source_File_Index>
1

> <s_m_Source_File>
2c23.sdf

> <s_m_Source_Path>
/Users/azimis/shpc/lsfe/TYK2

> <s_m_entry_id>
3

> <s_m_entry_name>
2c23.1

$$$$
74 changes: 74 additions & 0 deletions examples/RSFE/TYK2-JAK2/ligands/c41.sdf
View file
Open in desktop
Original file line number Diff line number Diff line change
@@ -0,0 +1,74 @@
1_cpd41
3D
Schrodinger Suite 2024-2.
26 27 0 0 1 0 999 V2000
13.2760 -13.0620 22.0340 C 0 0 0 0 0 0
12.1370 -12.4170 21.5720 C 0 0 0 0 0 0
11.7970 -12.4610 20.2180 C 0 0 0 0 0 0
14.7060 -12.9920 27.7390 C 0 0 0 0 0 0
13.6610 -12.9300 23.4770 C 0 0 0 0 0 0
13.9570 -14.0250 25.6640 C 0 0 0 0 0 0
14.0870 -15.2770 26.2900 C 0 0 0 0 0 0
14.5140 -15.3480 27.6320 C 0 0 0 0 0 0
14.2780 -12.8750 26.4110 C 0 0 0 0 0 0
13.5840 -13.9900 24.2990 N 0 0 0 0 0 0
14.8050 -14.2230 28.3190 N 0 0 0 0 0 0
15.1020 -14.2940 29.2817 H 0 0 0 0 0 0
14.1190 -13.7040 21.1270 C 0 0 0 0 0 0
15.0110 -11.9570 28.3750 O 0 0 0 0 0 0
14.0140 -11.8110 23.8220 O 0 0 0 0 0 0
15.6080 -14.5220 21.6930 Cl 0 0 0 0 0 0
13.7920 -13.7510 19.7690 C 0 0 0 0 0 0
11.0950 -11.5550 22.7400 Cl 0 0 0 0 0 0
12.6280 -13.1290 19.3160 C 0 0 0 0 0 0
10.8943 -11.9795 19.8720 H 0 0 0 0 0 0
13.8601 -16.1803 25.7432 H 0 0 0 0 0 0
14.6104 -16.3077 28.1180 H 0 0 0 0 0 0
14.1928 -11.8997 25.9551 H 0 0 0 0 0 0
13.2314 -14.8716 23.9546 H 0 0 0 0 0 0
14.4391 -14.2672 19.0753 H 0 0 0 0 0 0
12.3697 -13.1641 18.2679 H 0 0 0 0 0 0
1 2 2 0 0 0
1 5 1 0 0 0
1 13 1 0 0 0
2 3 1 0 0 0
2 18 1 0 0 0
3 19 2 0 0 0
3 20 1 0 0 0
4 9 1 0 0 0
4 11 1 0 0 0
4 14 2 0 0 0
5 10 1 0 0 0
5 15 2 0 0 0
6 7 1 0 0 0
6 9 2 0 0 0
6 10 1 0 0 0
7 8 2 0 0 0
7 21 1 0 0 0
8 11 1 0 0 0
8 22 1 0 0 0
9 23 1 0 0 0
10 24 1 0 0 0
11 12 1 0 0 0
13 16 1 0 0 0
13 17 2 0 0 0
17 19 1 0 0 0
17 25 1 0 0 0
19 26 1 0 0 0
M END
> <i_m_Source_File_Index>
1

> <s_m_Source_File>
1c41.sdf

> <s_m_Source_Path>
/Users/azimis/shpc/lsfe/TYK2_inputs

> <s_m_entry_id>
42

> <s_m_entry_name>
1c41.1

$$$$
95 changes: 95 additions & 0 deletions examples/RSFE/TYK2-JAK2/ligands/c46.sdf
View file
Open in desktop
Original file line number Diff line number Diff line change
@@ -0,0 +1,95 @@
1_cpd46
3D
Schrodinger Suite 2024-2.
36 38 0 0 1 0 999 V2000
13.2563 -13.5590 22.2350 C 0 0 0 0 0 0
14.1674 -14.1348 21.3288 C 0 0 0 0 0 0
13.9534 -14.0570 19.9591 C 0 0 0 0 0 0
14.6467 -14.5211 19.2733 H 0 0 0 0 0 0
14.2636 -12.6805 25.7620 C 0 0 0 0 0 0
13.5160 -13.7538 23.6770 C 0 0 0 0 0 0
14.3518 -13.8088 26.6049 C 0 0 0 0 0 0
14.0602 -14.7861 26.2496 H 0 0 0 0 0 0
14.8230 -13.6362 27.9054 C 0 0 0 0 0 0
14.9235 -14.4913 28.5575 H 0 0 0 0 0 0
12.1377 -12.8649 21.7363 C 0 0 0 0 0 0
12.8450 -13.3803 19.4784 C 0 0 0 0 0 0
12.6785 -13.3110 18.4136 H 0 0 0 0 0 0
11.9428 -12.7881 20.3608 C 0 0 0 0 0 0
11.0825 -12.2634 19.9721 H 0 0 0 0 0 0
15.5928 -14.9077 21.9249 Cl 0 0 0 0 0 0
13.4021 -14.8922 24.1426 O 0 0 0 0 0 0
13.9110 -12.6989 24.4099 N 0 0 0 0 0 0
13.9587 -11.8138 23.9257 H 0 0 0 0 0 0
15.1502 -12.4233 28.3493 N 0 0 0 0 0 0
15.0745 -11.3251 27.5964 C 0 0 0 0 0 0
14.6487 -11.4409 26.2703 C 0 0 0 0 0 0
14.6180 -10.5666 25.6369 H 0 0 0 0 0 0
15.4478 -10.0767 28.1412 N 0 0 0 0 0 0
16.0490 -10.0806 28.9528 H 0 0 0 0 0 0
15.0538 -8.8627 27.6491 C 0 0 0 0 0 0
14.3398 -8.7850 26.6661 O 0 0 0 0 0 0
15.5130 -7.5785 28.3279 C 0 0 0 0 0 0
16.1466 -8.1335 29.0198 H 0 0 0 0 0 0
15.6847 -6.3115 27.4788 C 0 0 0 0 0 0
16.5032 -5.6226 27.6877 H 0 0 0 0 0 0
15.5056 -6.3477 26.4042 H 0 0 0 0 0 0
14.5136 -6.4214 28.4511 C 0 0 0 0 0 0
13.4987 -6.5357 28.0703 H 0 0 0 0 0 0
14.4963 -5.8107 29.3538 H 0 0 0 0 0 0
11.0138 -12.0539 22.7836 Cl 0 0 0 0 0 0
1 2 2 0 0 0
1 6 1 0 0 0
1 11 1 0 0 0
2 3 1 0 0 0
2 16 1 0 0 0
3 4 1 0 0 0
3 12 2 0 0 0
5 7 1 0 0 0
5 18 1 0 0 0
5 22 2 0 0 0
6 17 2 0 0 0
6 18 1 0 0 0
7 8 1 0 0 0
7 9 2 0 0 0
9 10 1 0 0 0
9 20 1 0 0 0
11 14 2 0 0 0
11 36 1 0 0 0
12 13 1 0 0 0
12 14 1 0 0 0
14 15 1 0 0 0
18 19 1 0 0 0
20 21 2 0 0 0
21 22 1 0 0 0
21 24 1 0 0 0
22 23 1 0 0 0
24 25 1 0 0 0
24 26 1 0 0 0
26 27 2 0 0 0
26 28 1 0 0 0
28 29 1 0 0 0
28 30 1 0 0 0
28 33 1 0 0 0
30 31 1 0 0 0
30 32 1 0 0 0
30 33 1 0 0 0
33 34 1 0 0 0
33 35 1 0 0 0
M END
> <i_m_Source_File_Index>
1

> <s_m_Source_File>
1c46.sdf

> <s_m_Source_Path>
/Users/azimis/shpc/lsfe/TYK2

> <s_m_entry_id>
2

> <s_m_entry_name>
1c46.1

$$$$
Loading