Solvation Free Energies of Drug-like Molecules via Fast Growth in an Explicit Solvent: Assessment of the AM1-BCC, RESP/HF/6–31G*, RESP-QM/MM, and ABCG2 Fixed-Charge Approaches

We assess the performance of the nonequilibrium alchemical fast-growth method in calculating water and 1-octanol solvation free energies, comparing the recently proposed ABCG2 model with other empirical and quantum mechanics (QM)-based approaches for modeling electrostatic interactions in condensed phases using fixed atomic charges. The fixed-charge protocols are tested on the challenging set of drug-like polyfunctional molecules previously used by Vassetti et al., J. Chem. Theory Comput. 2019, 15, 1983–1995, broadly spanning the chemical space and often exhibiting complex conformational landscapes. We find that the cost-effective empirical ABCG2 protocol consistently outperforms the AM1/BCC precursor model and the widely used HF/6–31G* ab initio charge derivation method, achieving solvation free energy accuracy comparable to an expensive QM/MM-based methodology for atomic fixed charge determination. For water-octanol transfer free energies, ABCG2 benefits from systematic error cancellation, yielding remarkable agreement with experimental data, exhibiting excellent Pearson and Kendall rank coefficients and a mean unsigned error below 1 kcal/mol, matching the performance of the costly QM/MM approach. These results suggest that the ABCG2 protocol holds great promise for the high-throughput in silico prediction of ligand-protein binding free energies in drug discovery projects.