Accurate absolute free energies for ligand–protein binding

The accurate calculation of the binding free energy for arbitrary ligand–protein pairs is a considerable challenge in computer-aided drug discovery. Recently, it has been demonstrated that current state-of-the-art molecular dynamics (MD) based methods are capable of making highly accurate predictions. Conventional MD-based approaches rely on the first principles of statistical mechanics and assume equilibrium sampling of the phase space. In the current work we demonstrate that accurate absolute binding free energies (ABFE) can also be obtained via theoretically rigorous non-equilibrium approaches.


Fig: Overview of the investigated systems: a Set of 11 ligands binding to the bromodomain BRD4(1) assembled in ref. 7. bSet of 22 bromodomain complexes with the ligand bromosporine assembled in ref. 12. c Crystallographic structure of T4 lysozyme complexed with a ligand (4w57). The inset shows an enlarged binding site of the aligned apo (4w51, orange) and holo (4w57, blue) structures, highlighting the major loop motion upon ligand binding. Also shown are 5 ligands binding to T4 lysozyme that were investigated in this work.

Our investigation of ligands binding to bromodomains and T4 lysozyme reveals that both equilibrium and non-equilibrium approaches converge to the same results. The non-equilibrium approach achieves the same level of accuracy and convergence as an equilibrium free energy perturbation (FEP) method enhanced by Hamiltonian replica exchange. We also compare uni- and bi-directional non-equilibrium approaches and demonstrate that considering the work distributions from both forward and reverse directions provides substantial accuracy gains. In summary, non-equilibrium ABFE calculations are shown to yield reliable and well-converged estimates of protein–ligand binding affinity.

Gapsys, V., Yildirim, A., Aldeghi, M. et al. Accurate absolute free energies for ligand–protein binding based on non-equilibrium approaches. Commun Chem 4, 61 (2021).

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