transformato

transformato performs large-scale relative binding free energy calculations for small molecules that share a common core scaffold by setting up alchemical transformations to estimate relative binding and solvation free energies.

Key Features:

• Common Core Scaffold Approach: Both ligands are mutated to a shared core structure to avoid direct L1→L2 transformations and minimize dummy atoms, which are only present at intermediate states.
• Alchemical Transformation Path Setup: Constructs alchemical transformation paths that mutate two ligands into a common core structure.
• MD Engine Support: Generates inputs for and supports simulations with OpenMM, CHARMM, and CHARMM/OpenMM.
• Separation of Logic and Input Generation: Architecture separates program logic from input generation to enable extension to additional engines.
• Hydrogen Mass Reweighting: Produces results with and without hydrogen mass reweighting.
• Implementation: Implemented in Python.
• Validation and Performance Metrics: Validation across five protein–ligand systems included 76 relative binding free energy differences with an overall RMSE of 1.17 kcal/mol and Pearson correlation 0.73 versus experiment.
• Independence from Chosen Core: For selected cases, relative ΔΔG values were confirmed to be independent of the chosen intermediate common core structure.

Scientific Applications:

• Relative Binding Free Energy Estimation: Estimation of relative binding free energies (ΔΔG) for protein–ligand pairs within congeneric series sharing a common core.
• Solvation Free Energy Estimation: Calculation of relative solvation free energies via alchemical transformations.
• Method Benchmarking and Validation: Benchmarking and validation of alchemical free energy calculation methods against experimental binding free energies.
• Large-Scale Congeneric Series Studies: Large-scale computation of relative free energies for congeneric ligand series in computational chemistry and drug discovery research.

Methodology:

Sets up alchemical transformation paths that mutate pairs of ligands to a shared core, generates inputs for OpenMM, CHARMM, and CHARMM/OpenMM, supports hydrogen mass reweighting, and confines dummy atoms to intermediate alchemical states.