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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
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Large scale relative protein ligand binding affinities using non-equilibrium alchemy.

Vytautas Gapsys1, Laura Pérez-Benito2, Matteo Aldeghi1

  • 1Computational Biomolecular Dynamics Group, Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry D-37077 Göttingen Germany bgroot@gwdg.de.

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This study introduces an open-source method for calculating ligand binding affinities using molecular dynamics (MD) simulations. The new approach simplifies alchemical calculations, achieving high accuracy comparable to commercial software for drug design.

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Area of Science:

  • Computational chemistry
  • Molecular modeling
  • Drug discovery

Background:

  • Alchemical free energy calculations using molecular dynamics (MD) simulations are powerful for drug design.
  • Complex setup procedures hinder the widespread adoption of these methods.
  • Limited end-to-end open-source tools are available.

Purpose of the Study:

  • To present an accessible, open-source approach for alchemical free energy calculations.
  • To enable easy setup and execution of calculations for diverse small molecules.
  • To validate the method's performance against established commercial tools.

Main Methods:

  • Utilized the open-source software pmx with the GROMACS MD engine.
  • Employed non-equilibrium thermodynamic integration (TI) for calculations.
  • Combined results from Amber and Charmm force fields for consensus outcomes.

Main Results:

  • Achieved high precision and accuracy in relative protein-ligand alchemical free energy calculations.
  • Demonstrated performance on par with the commercial FEP+ approach.
  • Obtained an average unsigned error (AUE) of 3.64 ± 0.14 kJ mol⁻¹ on a large dataset of 482 perturbations.

Conclusions:

  • The presented pmx-based method offers a user-friendly, open-source alternative for alchemical free energy calculations.
  • This approach facilitates broader application of accurate binding affinity predictions in drug design.
  • The consensus results from multiple force fields enhance the reliability of the predictions.