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Binding Free Energies without Alchemy

Michael Brocidiacono, Brandon Novy, Rishabh Dey, Konstantin I. Popov, Alexander Tropsha

Abstract

Absolute Binding Free Energy (ABFE) methods are among the most accurate computational techniques for predicting protein-ligand binding affinities, but their utility is limited by the need for many simulations of alchemically modified intermediate states. We propose Direct Binding Free Energy (DBFE), an end-state ABFE method in implicit solvent that requires no alchemical intermediates. DBFE outperforms OBC2 double decoupling on a host-guest benchmark and performs comparably to OBC2 MM/GBSA on a protein-ligand benchmark. Since receptor and ligand simulations can be precomputed and amortized across compounds, DBFE requires only one complex simulation per ligand compared to the many lambda windows needed for double decoupling, making it a promising candidate for virtual screening workflows. We publicly release the code for this method at https://github.com/molecularmodelinglab/dbfe.

Binding Free Energies without Alchemy

Abstract

Absolute Binding Free Energy (ABFE) methods are among the most accurate computational techniques for predicting protein-ligand binding affinities, but their utility is limited by the need for many simulations of alchemically modified intermediate states. We propose Direct Binding Free Energy (DBFE), an end-state ABFE method in implicit solvent that requires no alchemical intermediates. DBFE outperforms OBC2 double decoupling on a host-guest benchmark and performs comparably to OBC2 MM/GBSA on a protein-ligand benchmark. Since receptor and ligand simulations can be precomputed and amortized across compounds, DBFE requires only one complex simulation per ligand compared to the many lambda windows needed for double decoupling, making it a promising candidate for virtual screening workflows. We publicly release the code for this method at https://github.com/molecularmodelinglab/dbfe.
Paper Structure (8 sections, 3 equations, 4 figures, 2 tables)

This paper contains 8 sections, 3 equations, 4 figures, 2 tables.

Table of Contents

  1. Introduction
  2. Methods
  3. Intuition
  4. The Direct Binding Free Energy method
  5. Benchmarking DBFE
  6. Host-Guest Benchmark
  7. Protein-Ligand Benchmark
  8. Discussion

Figures (4)

  • Figure 1: The full thermodynamic cycle used by DBFE.
  • Figure 2: Comparison of all methods versus experimental $\Delta G$ on the host-guest benchmark. Each subplot shows predicted versus experimental binding free energies, with bootstrap metrics (RMSE, Pearson $r$, Spearman $\rho$) and 95% confidence intervals.
  • Figure 3: Comparison of all methods versus experimental $\Delta G$ on the protein-ligand benchmark. Each subplot shows predicted versus experimental binding free energies, with bootstrap metrics (RMSE, Pearson $r$, Spearman $\rho$) and 95% confidence intervals.
  • Figure 4: DBFE versus OBC2 double decoupling $\Delta G$ on both benchmarks. Left: host-guest benchmark. Right: protein-ligand benchmark.