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Non-equilibrium work switching simulations and Jarzynski's equation are a reliable method for computing free energy differences, ΔAlow→high, between two levels of theory, such as a pure molecular mechanical (MM) and a quantum mechanical/molecular mechanical (QM/MM) description of a system of interest. Despite the inherent parallelism, the computational cost of this approach can quickly become very high. This is particularly true for systems where the core region, the part of the system to be described at different levels of theory, is embedded in an environment such as explicit solvent water. We find that even for relatively simple solute-water systems, switching lengths of at least 5 ps are necessary to compute ΔAlow→high reliably. In this study, we investigate two approaches towards an affordable protocol, with an emphasis on keeping the switching length well below 5 ps. Inserting a hybrid charge intermediate state with modified partial charges, which resembles the charge distribution of the desired high level, makes it possible to obtain reliable calculations with 2 ps switches. Attempts using step-wise linear switching paths, on the other hand, did not lead to improvement, i.e., a faster convergence for all systems. To understand these findings, we analyzed the solutes' properties as a function of the partial charges used and the number of water molecules in direct contact with the solute, and studied the time needed for water molecules to reorient themselves upon a change in the solute's charge distribution.

Indirect (S)QM/MM free energy simulations (FES) are vital to efficiently incorporating sufficient sampling and accurate (QM) energetic evaluations when estimating free energies of practical/experimental interest. Connecting between levels of theory, i.e., calculating Δ A l o w → h i g h , remains to be the most challenging step within an indirect FES protocol. To improve calculations of Δ A l o w → h i g h , we must: (1) compare the performance of all FES methods currently available; and (2) compile and maintain datasets of Δ A l o w → h i g h calculated for a wide-variety of molecules so that future practitioners may replicate or improve upon the current state-of-the-art. Towards these two aims, we introduce a new dataset, "HiPen", which tabulates Δ A g a s M M → 3 o b (the free energy associated with switching from an M M to an S C C - D F T B molecular description using the 3 ob parameter set in gas phase), calculated for 22 drug-like small molecules. We compare the calculation of this value using free energy perturbation, Bennett's acceptance ratio, Jarzynski's equation, and Crooks' equation. We also predict the reliability of each calculated Δ A g a s M M → 3 o b by evaluating several convergence criteria including sample size hysteresis, overlap statistics, and bias metric ( Π ). Within the total dataset, three distinct categories of molecules emerge: the "good" molecules, for which we can obtain converged Δ A g a s M M → 3 o b using Jarzynski's equation; "bad" molecules which require Crooks' equation to obtain a converged Δ A g a s M M → 3 o b ; and "ugly" molecules for which we cannot obtain reliably converged Δ A g a s M M → 3 o b with either Jarzynski's or Crooks' equations. We discuss, in depth, results from several example molecules in each of these categories and describe how dihedral discrepancies between levels of theory cause convergence failures even for these gas phase free energy simulations.