Obtaining QM/MM binding free energies in the SAMPL8 drugs of abuse challenge: indirect approaches

Accurately predicting free energy differences is essential in realizing the full potential of rational drug design. Unfortunately, high levels of accuracy often require computationally expensive QM/MM Hamiltonians. Fortuitously, the cost of employing QM/MM approaches in rigorous free energy simulation can be reduced through the use of the so-called indirect approach to QM/MM free energies, in which the need for QM/MM simulations is avoided via a QM/MM correction at the classical endpoints of interest. Herein, we focus on the computation of QM/MM binding free energies in the context of the SAMPL8 Drugs of Abuse host-guest challenge. Of the 5 QM/MM correction coupled with force-matching submissions, PM6-D3H4/MM ranked submission proved the best overall QM/MM entry, with an RMSE from experimental results of 2.43 kcal/mol (best in ranked submissions), a Pearson's correlation of 0.78 (second-best in ranked submissions), and a Kendall tau correlation of 0.52 (best in ranked submissions).

Automated summary

Accurately predicting free energy differences is crucial for rational drug design. This study focuses on the computation of QM/MM binding free energies and evaluates different QM/MM correction methods in the context of the SAMPL8 Drugs of Abuse host-guest challenge.