Ligand Bound and Unbound Equilibration for NES [MDPrep] [MDRun]

Category Paths

Follow one of these paths in the Orion user interface, to find the floe.

  • Product-based/Molecular Dynamics/GROMACS

  • Product-based/Molecular Dynamics/OpenMM

  • Role-based/Computational Chemist

  • Role-based/Medicinal Chemist

  • Task-based/Molecular Dynamics

  • Solution-based/Hit to Lead/Target Preparation/Generic MD simulation


  • Purpose:

    • This Floe performs MD simulations given a prepared protein and a set of posed and prepared ligands, running both bound and unbound simulations of each ligand in preparation for relative binding free energy (RBFE) calculations using nonequilibrium switching (NES).

  • Method Recommendations/Requirements:

    • The ligands need to have reasonable 3D coordinates, all atoms, and correct chemistry (in particular bond orders and formal charges).

    • Each ligand can have multiple conformers but each conformer will be run separately as a different ligand.

    • The starting poses should not have very high gradients, in particular no bad clashes with the protein.

    • The protein needs to be prepared to MD standards: protein chains must be capped, all atoms in protein residues (including hydrogens) must be present, and missing protein loops resolved or capped.

    • Crystallographic internal waters should be retained where possible.

  • Limitations

    • Currently this Floe cannot handle covalent bonds between different components such as ligand, protein, and cofactors.

    • Glycosylation on proteins is truncated and the amino acid is capped with H.

  • Expertise Level:

    • Regular/Intermediate/Advanced

  • Compute Resource:

    • Depends on simulation length; Minimal resources for default 6 ns.

  • Keywords:

    • MD, MDPrep

  • Related Floes:

    • Bound Protein-Ligand MD [MDPrep] [MD]

    • Short Trajectory MD with Analysis [MDPrep] [MD] [MDAnalysis]

Given the inputs of the protein and posed ligands, the complex is formed with each ligand/conformer separately, and the bound and unbound simulations are then carried out. Currently only one of the conformers will be used in the NES calculations. A minimization stage is performed on the system followed by a warm up (NVT ensemble) and several equilibration stages (NPT ensemble). In the minimization, warm up, and equilibration stages, positional harmonic restraints are applied on the ligand and protein. At the end of the equilibration stages a production run (by default 6 ns) is performed on the unrestrained system. Two datasets are written, one for the bound and one for the unbound ligands.

Promoted Parameters

Title in user interface (promoted name)


Protein Input Dataset (protein): Protein Input Dataset

  • Type: data_source

Ligand Input Dataset (ligands): Ligands-only input dataset or protein-ligand input dataset containing Design Unit prepared by SPRUCE

  • Required

  • Type: data_source

CPU GPU Spot Policy Selection

CPUs (cpu_count_md): The number of CPUs to run this cube with

  • Type: integer

  • Default: 16

GPUs (gpu_count_md): The number of GPUs to run this cube with

  • Type: integer

  • Default: 1

Spot policy (spot_policy_md): Control cube placement on spot market instances

  • Type: string

  • Default: Preferred

  • Choices: [‘Allowed’, ‘Preferred’, ‘NotPreferred’, ‘Prohibited’, ‘Required’]

Complex Setup Parameters

Protein Name (flask_title): Prefix name used to identity the Protein. If not specified, it will use the title of the input protein.

  • Type: string

  • Default:

Assign Ligand Partial Charges (charge_ligands): Assign Ligand Partial Charges or not

  • Type: boolean

  • Default: True

  • Choices: [True, False]

Equilibration Setup Parameters

Ligand Force Field (ligand_ff): Force field to be applied to the ligand. The ‘OpenFF_2.0.0’, ‘OpenFF_1.3.1’, and ‘Custom’ force fields may be augmented with bespoke force field parameters by turning on ‘Use Bespoke Parameters When Available’ and providing SMIRNOFF format parameters on the input record.

  • Required

  • Type: string

  • Default: OpenFF_2.0.0

  • Choices: [‘Gaff_1.81’, ‘Gaff_2.11’, ‘OpenFF_1.1.1’, ‘OpenFF_1.2.1’, ‘OpenFF_1.3.1’, ‘OpenFF_2.0.0’, ‘Smirnoff99Frosst’, ‘Custom’]

Custom Ligand Force Field File (custom_offxml_file_in): One or more SMIRNOFF XML files defining the force field to be applied to the ligand. This input is required when ‘Ligand Force Field’ is set to ‘Custom’.

  • Type: file_in

Protein Force Field (protein_ff): Force field to be applied to the protein.

  • Required

  • Type: string

  • Default: Amber14SB

  • Choices: [‘Amber14SB’, ‘Amber99SB’, ‘Amber99SBildn’, ‘AmberFB15’]

MD Engine (md_engine): Select the available MD engine

  • Type: string

  • Default: OpenMM

  • Choices: [‘OpenMM’, ‘Gromacs’]

Hydrogen Mass Repartitioning (hmr_us): Give hydrogens more mass to speed up the MD

  • Type: boolean

  • Default: True

  • Choices: [True, False]

Equilibration Production Time (prod_us_ns): The Equilibration production running time in ns

  • Type: decimal

  • Default: 6.0