Edge Mapper for RBFE calculations

Category Paths

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

  • Product-based/Molecular Dynamics

  • Role-based/Computational Chemist

  • Role-based/Medicinal Chemist

  • Task-based/Data Science/Filtering

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

Description

  • Tutorials and Further Reading:

  • Purpose:

    • This floe produces ligand pairs or edges to run relative binding free energy (RBFE) calculations.

  • Method Recommendations/Requirements:

    • One input is required:

      • A ligand dataset. The provided ligands must have reasonable 3D coordinates, all atoms, and correct chemistry, such as bond orders and formal charges.

      • Optionally, the user can also import into the Edge Mapper Floe an externally generated map, to generate a mapper output dataset of only those edges defined by the external map. The syntax of this external map file is described below.

  • Limitations

    • The provided ligand set should contain similar ligands where a common scaffold is used and functional groups are added to it. Large scaffold mutations should be avoided to improve RBFE and ABFE result errors.

  • Expertise Level:

    • Regular

  • Compute Resource:

    • Low

  • Keywords:

    • MD, FECalc

  • Related Floes:

    • FE-NES for Binding Affinity Prediction

Given n ligands, out of all possible n(n-1)/2 edges, the Edge Mapper Floe selects a reasonable subset of the edges, with the goal of keeping the computational demand low and providing a high probability of giving accurate RBFE calculations.

The floe offers four map types: (1) OELOMAP; (2) Star map; (3) Binary star map; and (4) Multi-star map.

  1. OELOMAP: Based on the assumption that the more similar the ligands in the edge are, the more accurate the free energy difference estimation is, edges are selected based on a set of heuristics for chemical similarity measures, including the MCS, ROCS similarity, and the equal charge check.

  2. Star map: star map with a center ligand (hub).

  3. Binary star map: star map with two center ligands and an axle edge.

  4. Multi-star map: clustering-based perturbation map with multiple stars.

If Star map or Binary star map is selected, a user is expected to provide the name(s) of the hub (reference) ligand(s), or the hubs will be automatically selected. If the specified hub ligand name does not exist in the provided ligand set, it will also auto-select the hub. The choice of hub for a star map is the dominant factor in the performance of that map. Currently, for the star map, the representative parent molecule will be selected as a hub ligand and for the binary star map, the two hubs will be selected based on the similarities to other ligands.

The output floe report shows the similarity scores as numbers in the range [0,1]. The higher the score, the more similar the ligands in the edge. The output can be used with the FE-NES Floe to run RBFE calculations.

Additionally, the Edge Mapper Floe can accept an edge text input file as well. In this case, the produced map is defined in the provided text file and no attempt to use internal heuristics is done. The text file of edges describes the map of desired alchemical transformations of one ligand into another; each transformation forms an edge of a connected graph of ligands. The file must have one line per transformation of the format:

ligA_name >> ligB_name

where “ligA_name” and “ligB_name” are the ligand title names for the ligands to be transformed. These ligand names must correspond exactly to those in the provided ligand set.

Promoted Parameters

Title in user interface (promoted name)

Inputs

Ligand Dataset (ligands): Dataset of records where each ligand is saved as the primary molecule.

  • Required

  • Type: data_source

Map type (map_type): If ‘Star map’ or ‘Binary star map’ is selected, a user is expected to provide the name(s) of the hub (reference) ligand(s), or the hub(s) will be automatically selected.

  • Type: string

  • Default: OELOMAP

  • Choices: [‘OELOMAP’, ‘Star map’, ‘Binary star map’, ‘Multi-star map’]

Outputs

Edge Mapper Output Dataset (mapper_out): Output dataset containing edges generated by the selected map type or provided by the user via a text file.

  • Type: dataset_out

  • Default: edge_map

All Possible Edges Output Dataset (all_out):

Optional output dataset of all N*(N-1)/2 possible edges. This dataset is generated only if the Write All Possible Edges parameter of the Edge Mapper Cube is set to On.

  • Type: dataset_out

  • Default: all_possible_edges

Edge Map Diagram (edge_map_floe_report): Title for the edge map diagram floe report.

  • Type: string

  • Default: Edge Map Diagram

Interactive Edge Map Diagram (int_edge_map_floe_report): Title for the interactive edge map diagram floe report.

  • Type: string

  • Default: Interactive Edge Map Diagram

Optional Inputs

Optional Ligand Edge Map File (edges): A user-defined ligand edge map text file.

  • Type: file_in

Star Map Parameters

Star Map Hubs (hub): Applicable only to Star Map and Binary Star Map. Optionally provide the names of hub ligands. If no hubs are specified, they will be selected automatically.

  • Type: string

  • Default: [‘’]