The indirect approach to free energy is by and large one of the most common methods in efficient free energy calculation. Although it is an attractive choice, recent findings by many have demonstrated difficulty in converging the end state energetic correction, ΔAMM→QM, due to configurational disparity in stiff degrees of freedom. This is painfully obvious when the computation is done using free energy perturbation (FEP). Two viable solutions exist: use a more accurate low level of theory -- such as a semi-empirical method -- which is not always plausible, or use a more robust one sided approach in computing ΔAMM→QM. Towards that latter aim, we demonstrate that use of non-equilibrium work (NEW) between MM and QM in standard free energy formalisms (e.g. Jarzysnki's equation) provides a rigorous approach to effectively generating ΔAMM→QM. Results in free simulation of blocked amino acids and umbrella sampling of the butane dihedral profile prove that use of NEW methods are an accurate and more efficient way of connecting levels of theory than standard indirect equilibrium approaches.

Equilibrium free energy differences between high and low levels of theory via non-equilibrium work approaches

251st National Meeting (2016)

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