OpenFE Relative Binding Free Energies

Relative binding free energies for a congeneric ligand series with OpenFE: upload the ligands and a prepared protein, get ddG per edge and dG per ligand.

by Temple Compute

Run OpenFE Relative Binding Free Energies on Horus

W-37 · OpenFE Relative Binding Free Energies (TYK2)

Relative binding free energies for a congeneric ligand series with OpenFE: upload the ligands and a prepared protein, get ddG per edge and dG per ligand.

Domain: OMSF

Overview

Relative binding free energies (RBFE) for a congeneric TYK2 inhibitor series with OpenFE 1.13.0, ported from the OpenFE rbfe_tutorial and cli_charge_molecules tutorials in the OMSF workflow directory. The quickrun task is a horus_map with one clone per transformation JSON (complex or solvent leg of each edge). With the 10 default ligands that is 9 edges and 18 legs. The workflow has 5 tasks.

Pipeline

charge_ligands  openfe charge-molecules (AM1-BCC)          --> results/charged_ligands.sdf
plan_network    Kartograf + minimal spanning network       --> results/transformations/<leg>.json, results/ligand_network.graphml
quickrun        openfe quickrun per leg                    --> results/legs/<slot>/result.json
gather          openfe gather                              --> results/ddg.tsv, results/raw.tsv, results/dg.tsv
report          tables + Mol* view                         --> results/report.html

Inputs / Outputs

ligands: SDF with 3D poses in the binding site; every record is charged and planned (default examples/tyk2_ligands.sdf).
protein: prepared PDB (default examples/tyk2_protein.pdb).
results/ddg.tsv: ddG per edge with uncertainty. results/raw.tsv: dG per leg and repeat. results/dg.tsv: MLE dG per ligand.
results/report.html: both tables, network edges and a Mol* view of the protein with the ligands, titled with target_name.
results/ligand_network.graphml, results/charged_ligands.sdf, results/transformations/, results/legs/<slot>/ (result.json, quickrun.log).
results/dg.tsv needs at least 3 edges and 2 repeats per edge; otherwise it holds a one-line note and the report shows ddG and raw values.

Parameters

Defaults are the openfe 1.13.0 RelativeHybridTopologyProtocol defaults.

| id | Default | Meaning | |---|---|---| | ligands / protein | TYK2 examples | Inputs above | | target_name | TYK2 | Protein label in the report title and Mol* view | | n_repeats | 3 | Repeats per leg (1-10); dg needs >= 2 | | lambda_windows | 11 | Lambda windows per leg (2-32); n_replicas is set equal | | equilibration_ns | 1.0 | Equilibration per replica (0.1-20) | | production_ns | 5.0 | Production per replica (0.5-50) | | time_per_iteration_ps | 2.5 | MD time between replica-exchange attempts (0.5-10); must divide the lengths and intervals | | minimization_steps | 5000 | Minimization steps before equilibration (0-100000) | | real_time_analysis_ps | 250 | Online free energy analysis interval (0-5000); 0 turns it off | | checkpoint_interval_ns | 1.0 | Checkpoint interval, the --resume restart point (0.25-10) | | compute_platform | cuda | OpenMM platform: cuda, opencl or cpu |

References

OpenFE
OpenMM
OpenFE docs
OpenFE ExampleNotebooks (upstream tutorials, MIT)
OMSF workflow directory
Workflow glue is MIT; the TYK2 inputs and tutorials are from OpenFreeEnergy/ExampleNotebooks (MIT) and openfe is MIT. Credit to the Open Free Energy team.