RBFE¶

This document describes how to prepare systems and plan ligand networks for RBFE (relative binding free energy) workflows using Deep Origin tools.

Prerequisites¶

We assume a protein and two ligands you want to compare. In this tutorial we use the BRD4 example dataset.

from deeporigin.drug_discovery import (
    BRD_DATA_DIR,
    Ligand,
    Protein,
    SystemPrep,
)

protein = Protein.from_file(BRD_DATA_DIR / "brd.pdb")
protein.sync()

ligand1 = Ligand.from_sdf(BRD_DATA_DIR / "brd-2.sdf")
ligand1.sync()

ligand2 = Ligand.from_sdf(BRD_DATA_DIR / "brd-3.sdf")
ligand2.sync()

For more details on how to get started, see Getting Started.

System preparation¶

Before RBFE, prepare simulation-ready systems for the protein–ligand pair. SystemPrep accepts two ligands and runs RBFE-oriented preparation (binding and solvation legs for both ligands).

sysprep = SystemPrep(
    protein=protein,
    ligand1=ligand1,
    ligand2=ligand2,
)

prepared = sysprep.run()
prepared.show()

The returned PreparedSystem includes paths to binding and solvation XML files and a system PDB. Submit batch RBFE with the RBFE class and platform tool deeporigin.rbfe:

from deeporigin.drug_discovery import RBFE, RBFEParams

# End-to-end: prep + FEP for one pair (add more pairs to the list for networks)
rbfe = RBFE(
    protein=protein,
    pairs=[(ligand1, ligand2)],
    params=RBFEParams(test_run=1),
)
rbfe.start()

For FEP on existing prepared systems, pass prepared_systems=[prepared, ...] (steps is inferred as ["rbfe"]). For single-pair prep without FEP, use SystemPrep instead of RBFE. See Platform executions.

Constructing a network¶

For a congeneric series, submit the full ligand set and let the workflow run Konnektor to plan pairwise edges, then system-prep and RBFE for each edge:

from deeporigin.drug_discovery import LigandSet

ligand_set = LigandSet.from_dir(BRD_DATA_DIR)
for ligand in ligand_set:
    ligand.sync()

rbfe = RBFE(
    protein=protein,
    ligands=ligand_set,
    network_type="mst",
    params=RBFEParams(test_run=1),
)
rbfe.start()

See the RBFE many-ligands workflow notebook for an end-to-end example on dev. For cycle closure with anchor ABFE values, see RBFE cycle-closure workflow.

To preview a network interactively in Jupyter before submitting, use Konnektor(ligands=...).run() and call .show_network() on the result — see constructing a network.