We benchmarked the predictive performance of absolute binding free energy methods on small molecule inhibitors targeting urokinase plasminogen activator, a serine protease regularly found overexpressed in metastatic tumors. Our ligand set includes highly charged, flexible, and titratable molecules that present a challenging case study evaluating the difficulties of modeling electrostatic and polarization effects in protein-ligand binding interactions. We exhaustively sample each inhibitor with ensemble MD trajectories composed of up to 5X 800ns replicates to compare the effectiveness of corrections applied to the standard thermodynamic integration (TI) scheme including: counter-ion removal to maintain system charge neutrality, pKa correction and constant pH simulations to account for multiple protonation states, ligand restraint strategies to improve convergence, and increasing salt concentration for electrostatic screening. Given the high computational cost and complexity associated with the TI method in setting up the intermediate state simulations required for sufficient sampling, we also studied the alternative end-state approach based on implicit Poisson-Boltzmann Surface Area (PBSA) solvation analysis. We demonstrate that the non-polar method can replicate the TI results without the complication of numerous intermediate state simulations and that scaling of the dielectric constant parameter can conveniently account for the impact of polarization without modifying the MD integrator. Our results provide a set of best-practices for the application of absolute binding free energy predictions that will accelerate the drug screening process and assessment of electrostatic and polarization effects that will contribute to method development for more accurate binding affinity predictions.

Electrostatics and polarization in protein-ligand binding affinity predictions

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.