Accurate absolute free energies for ligand-protein binding based on non-equilibrium approaches

Uppsala universitet, Science for Life Laboratory, SciLifeLab Uppsala universitet, Beräkningsbiologi och bioinformatik Max Planck Inst Biophys Chem, Computat Biomol Dynam Grp, Gottingen, Germany. Siirt Univ, Dept Phys, Siirt, Turkey. Vector Inst Artificial Intelligence, Toronto, ON, Canada. Max Planck Inst Biophys Chem, Computat Biomol Dynam Grp, Gottingen, Germany. Uppmax Max Planck Inst Biophys Chem, Computat Biomol Dynam Grp, Gottingen, Germany. NATURE RESEARCH 2021

Molecular dynamics-based approaches to calculate absolute protein-ligand binding free energy often rely on equilibrium free energy perturbation (FEP) protocols. Here, the authors study ligands binding to bromodomains and T4 lysozyme and find that both equilibrium and non-equilibrium approaches converge to the same results with the non-equilibrium method converging faster than FEP. 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. 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.

Theoretical Chemistry; Teoretisk kemi; Article in journal; info:eu-repo/semantics/article; text

10.1038.s42004-021-00498-y

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English

UPE oai:DiVA.org:uu-445579
0000-0002-7659-8526
doi:10.1038/s42004-021-00498-y
ISI:000656226900004
1280662135

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