Efficient Computation of Free Energy Contributions for Association Reactions of Large Molecules.

Modern density functional theory (DFT) methods are capable of providing accurate association energies for supramolecular systems and even protein-ligand complexes. However, the calculation of the essential harmonic vibrational frequencies needed to obtain free energies is often too computationally demanding. In this work, the corresponding thermostatistical contributions are computed in the well-established (modified) rigid-rotor-harmonic-oscillator approximation with structures and frequencies taken from low-cost quantum chemical methods, namely, GFN2-xTB and PM6-D3H4. Additionally, a recently developed new general force field (GFN-FF) is tested for this purpose. DFT reference values for 59 complexes composed of three standard noncovalent and supramolecular benchmark sets (S22, L7, and S30L) are used in the evaluation. Overall, the accuracy of the low-cost methods is remarkable with typical deviations of only 0.5-2 kcal mol (5-10%) from the DFT reference values. In particular, the performance of the GFN-FF is promising considering the acceleration of 5 and 2-3 orders of magnitude compared to DFT and GFN2-xTB, respectively. This opens new perspectives for computing thermodynamic properties of, e.g., biomacromolecules as shown, for example, for the binding of retinol and rivaroxaban in protein complexes consisting of ≤4700 atoms.