Nonequilibrium Switching [MDRun] [FECalc]

Category Paths

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

  • Product-based/Molecular Dynamics/GROMACS

  • Role-based/Computational Chemist

  • Role-based/Medicinal Chemist

  • Task-based/Molecular Dynamics

  • Task-based/Affinity Prediction

  • Solution-based/Hit to Lead/Affinity Prediction/Free-Energy Calculations

  • Solution-based/Small Molecule Lead-opt/Affinity

Description

  • Purpose:

    • This floe performs relative binding free energy (RBFE) calculations using the nonequilibrium switching (NES) method refined by the de Groot lab (Gapsys et al., Chem. Sci., 2020, 11, 1140-1152).

  • Method Recommendations/Requirements:

    • Four inputs are required:

      • An Orion dataset containing an equilibrium run for each bound ligand participating in the NES run.

      • An Orion dataset containing an equilibrium run for each unbound ligand participating in the NES run.

      • A Orion Dataset containing the ligand edges to run the RBFE calculation generated by using the Mapper Floe.

      • [Optional] a text file containing experimental binding free energies for at least one ligand, one experimental datapoint per line, of form “ligA_name {deltaG(exptl)} {error_deltaG(exptl)} {units}” for example, “gn1c -8.56 0.17 kcal/mol”.

  • Limitations

    • If no experimental binding free energies (the fourth input above) are given, the estimation of ligand binding free energies has no reference value so the relative values will be centered around the mean.

    • Currently, there is no mitigation for the effects of changes in buried waters, protein sidechain flips, or large protein movements between ligA and ligB.

  • Expertise Level:

    • Regular

  • Compute Resource:

    • High

  • Keywords:

    • MD, FECalc

  • Related Floes:

    • Ligand Bound and Unbound Equilibration for NES [MDPrep] [MD].

    • Equilibration and Nonequilibrium Switching [MDPrep] [MD] [FECalc].

    • Compare Experimental Affinity with NES Results [Utility] [FECalc].

    • Nonequilibrium Switching Recovery [Utility] [FECalc].

The floe will draw a number of starting snapshots from the bound and unbound trajectories of the ligands. Then for each edge in the edge file, it will generate an RBFE alchemical transformation from ligA into ligB, and carry out the NES fast transformation of ligA into ligB, and vice versa, for each of the snapshots. The resulting relative free energy change, or DeltaDeltaG, for each edge is the primary output of this method. A maximum likelihood estimator is then used to derive a predicted binding affinity (free energy, or DeltaG) for each ligand. The mean value of the input experimental binding free energies is used as the reference value for the computed ones.

The speed of the NES transformation and the number of snapshots transformed can be adjusted from default values by the user at runtime. The floe outputs two floe report/dataset pairs, one for the calculated RBFE edges (DeltaDeltaGs), and one for the derived affinity predictions (DeltaGs) of ligand.

Promoted Parameters

Title in user interface (promoted name)

  • Affinity Dataset (DG) type: dataset_out: Affinity Output Dataset
    Default: affinity_output_dataset
  • Bound Input Dataset (bound) type: data_source: Bound Input Dataset
  • Ligand Affinity Experimental file (exp) type: file_in: The ligand affinity experimental file with affinities in units of kcal/mol or kJ/mol
  • NES Failure Dataset (fail) type: dataset_out: NES Output Dataset Failure
    Default: fail_output_dataset
  • Mapper Dataset (map) type: data_source: Mapper Input Dataset
  • Max number of Mapper edges allowed (max_mapper_edges) type: integer: The max number of mapper edges allowed
    Default: 100
  • Optimize NES costs (nes_switch) type: boolean: Optimize NES costs by selecting to run the Bound Switching on cost effective instances
    Default: True
  • time (nes_time) type: decimal: NPT simulation time in nanoseconds
    Default: 0.05
  • NES Dataset (out) type: dataset_out: NES Dataset Out
    Default: nes_output_dataset
  • Recovery File (recovery) type: file_out: Recovery Output File
    Default: recovery_file
  • timestep_in_fs (timestep_in_fs) type: decimal: Time step (in femtoseconds) for MD integration
    Default: 2.0
    Choices: 1.0, 2.0
  • Total number of NES trajectory frames (trajectory_frames) type: integer: The total number of trajectory frames to be used along the NE switching
    Default: 80
  • Unbound Input Dataset (unbound) type: data_source: Unbound Input Dataset

Optional parameters (promoted names)

  • Mapper Dataset (data_in) type: data_source: Mapper Input Dataset
  • Ligand Affinity Experimental file (lig_exp_file) type: file_in: The ligand affinity experimental file with affinities in units of kcal/mol or kJ/mol
  • Recovery File (file_name) type: file_out: Recovery Output File
    Default: recovery_file
  • NE switching time (time) type: decimal: The Nonequilibrium switching time in nanoseconds
    Default: 0.05
  • NES time step in femtoseconds (timestep_in_fs) type: decimal: Time step (in femtoseconds) for MD integration
    Default: 2.0
    Choices: 1.0, 2.0
  • Max number of Mapper edges allowed (max_mapper_edges) type: integer: The max number of mapper edges allowed
    Default: 100
  • trajectory_frames (trajectory_frames) type: integer: The total number of trajectory frames to run NES
    Default: 80
  • time (time) type: decimal: NPT simulation time in nanoseconds
    Default: 0.05
  • timestep_in_fs (timestep_in_fs) type: decimal: Time step (in femtoseconds) for MD integration
    Default: 2.0
    Choices: 1.0, 2.0
  • Output Dataset (nes_data_out) type: dataset_out: Output dataset to write to
    Default: nes_output_dataset
  • NES Dataset (data_out) type: dataset_out: NES Dataset Out
    Default: nes_output_dataset
  • Affinity Dataset (data_out) type: dataset_out: Affinity Output Dataset
    Default: affinity_output_dataset
  • Unbound Input Dataset (data_in) type: data_source: Unbound Input Dataset
  • Total number of NES trajectory frames (trajectory_frames) type: integer: The total number of trajectory frames to be used along the NE switching
    Default: 80
  • Optimize NES costs (switch) type: boolean: Optimize NES costs by selecting to run the Bound Switching on cost effective instances
    Default: True
  • Bound Input Dataset (data_in) type: data_source: Bound Input Dataset
  • NES Failure Dataset (data_out) type: dataset_out: NES Output Dataset Failure
    Default: fail_output_dataset
  • time (time) type: decimal: NPT simulation time in nanoseconds
    Default: 0.05
  • timestep_in_fs (timestep_in_fs) type: decimal: Time step (in femtoseconds) for MD integration
    Default: 2.0
    Choices: 1.0, 2.0