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RBFE calculations with the alchemical transfer method

Relative binding free energy (RBFE) is a computational method used to predict the binding affinity of small molecules to protein targets. This method is widely used in drug discovery to identify potential drug candidates and optimize lead compounds. Acellera performs RBFE calculations using the alchemical transfer method (ATM), which involves transforming the ligand of interest into a reference ligand that is already known to bind to the protein target using an alchemical process. During the transformation, the ligand is gradually changed from the ligand of interest to the reference ligand, and the free energy difference between the two ligands is calculated.

The methodology offers several practical advantages while keeping the same performance as similar alchemical free energy methods. It does not need any soft-core pair potentials or modifications to the energy routines of the molecular dynamics engine, allowing us to use any force field for the simulations. In addition, it does not require the separation of binding free energy calculations into receptor and solvation legs or into electrostatic and non-electrostatic steps, so it can handle charged molecules.

Use Cases

  • Lead Optimization: RBFE can help researchers optimize lead compounds by predicting how changes to a ligand’s chemical structure affect its binding affinity.
  • Scaffold Hopping: Find novel compounds with different chemical structures that retain or improve the biological activity of a reference compound.
  • Understanding the SAR: Gain insights into the molecular mechanisms of ligand binding and help researchers design new compounds with improved binding affinity.

 

Results

The protocol involves:

  • Ligand parameterization: The ligands of interest will be parameterized for the simulations.
  • System building: All possible ligand pairs will be put together in the same system with the target protein and solvated in a water box.
  • Hamiltonian replica exchange simulations: Production runs are performed across a sequence of alchemical states defined by a λ-dependent Hamiltonian and multistate thermodynamic reweighting methods.
  • Relative binding affinity prediction: Binding affinity differences are predicted based on the unbinned weighted histogram analysis method (UWHAM).

 

The result is a table of estimated free energy differences between the ligands of interest.