Theoretical and Computational Chemistry

Alchemical Absolute Protein-Ligand Binding Free Energies for Drug Design



Recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods in drug discovery. Accurately assessing absolute binding free energies remains a challenging endeavour, mostly limited to small model cases. We demonstrate accurate absolute binding free energy estimates for 128 pharmaceutically relevant ligands across 7 proteins using a highly parallelizable non-equilibrium method. These calculations also provide detailed physical insight into the structural determinants of binding, identifying subtle rotamer rearrangements between protein apo and holo states that are crucial for binding. The challenge behind absolute binding free energy calculations stems in large part from the need to explicitly account for the protein’s apo state. In this work we present several approaches to obtain apo state ensembles, including a novel rigorous method to generate protein-ligand ensembles for the ligand in its decoupled state. Altogether, we present an effective open-source protocol for prospective application in drug discovery.


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Supplementary material

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Supplementary Information
Outline of the NEQ method, relative binding free energies recalculated from absolute ones broken down by system, absolute binding free energies calculated using apo and holo structures for the decoupled state broken down by system, p38 loop motion and its effects on absolute binding free energy, effects of extended equilibration on tyk2 absolute binding free energies, comparison of uncertainties, descriptions of restraint generation and decorrelation methods, validation of decorelation approaches, details of parametrization and simulation conditions, numerical values for computed and experimental absolute binding free energies.