Interaction-restricted induced fit docking

Introduction

The induced fit simulation with interaction restrictions allow for biased exploration, where the simulation results are limited to those that fit the specified conditions, such as specific distance or angle between user-defined atoms.

Inputs

  • protein-ligand PDB file

  • input.yaml specifying angle and distance restrictions

Defaults

  • iterations: 1

  • pele steps: 500

Recommendations

  1. We recommend using at least 50 CPUs.

  2. Since interaction restrictions require a nested YAML file, you might encounter issues, if your YAML has incorrect indentation. Run a test simulation first (with test: true in your YAML file) to ensure everything works correctly or use one of YAML checkers available online, e.g. YAML Lint.

1. Complex Preparation

Prepare the system with Protein Preparation Wizard. We would usually recommend protonating the protein (obligatory), deleting water molecules more than 5Å away from ligands and ions as well as filling in missing loops and side chains. The system must contain the protein and the ligand, however, the latter can be placed anywhere as its position will be automatically randomised all around the specified initial site atom.

2. Input Preparation

Prepare the input file input.yml:

Users can define two types of conditions using the atom strings (format chain:resnum:atomname, e.g. A:2:CA) to select the atoms:

  • distance: Distance between two atoms, which can be limited to a user-defined maximum, minimum or both.

  • angle: Angle between three atoms with a user-defined maximum, minimum or both.

system: "complex.pdb" # Ligand-protein complex
resname: "LIG" # Ligand residue name in system
chain: "L" # Ligand chain ID

interaction_restrictions:
- distance:  # distance between the two atoms will not exceed 3 A
    max: 3
  atoms:
    - "A:318:OG1"   # chain A, residue number 318, atom OG1
    - "Z:201:O3"
- angle:  # angle between those three atoms will remain between 90 and 160 degrees
    min: 90
    max: 160
  atoms:
    - "A:318:OG1"
    - "A:318:HG1"
    - "Z:201:O3"
cpus: 50

For more optional flags please refer to optional flags.

3. Run simulation

To run the system launch the simulation with the following command:

python -m pele_platform.main input.yml

4. Output

Raw output

Trajectory and report files for each simulation are located in working_folder/output. That’s where you can find detailed information on each snapshot (PDB file, binding energy, metrics, etc.).

Selected poses

Clusters

Upon completion of the simulation, all trajectories are clustered based on ligand heavy atom coordinates. Then, a cluster representative with the best binding energy (or metric of your choice) is selected. Ranked cluster representatives can be found in:

working_folder/results/clusters

Best snapshots

In addition, top 100 structures with the best binding energy (or metric of your choice) are retrieved. This is done to ensure the clustering algorithm did not skip any valuable results. They are stored in:

working_folder/results/top_poses