The use of the most accurate (i.e., QM or QM/MM) levels of theory for free energy simulations (FES) is typically not possible. Primarily, this is because the computational cost associated with the extensive configurational sampling needed for converging FES is prohibitive. To ensure the feasibility of QM-based FES, the "indirect" approach is generally taken, i.e., necessitating the computation of ΔA(MM→QM). Ideally, this step is performed with standard Free Energy Perturbation (FEP) as it only requires simulations be carried out at the low level of theory, however, work from several groups over the past few years has conclusively shown that FEP is ill-suited to this task.  As such, several alternative strategies and approximations have arisen to mitigate difficulties with FEP. In this presentation, I will discuss our recently developments to this end with particular emphasis on (1) using more robust techniques to compute ΔA(MM→QM), (2) improving MM descriptions of QM systems, and (3) critically examining a common approximation (i.e., the Interaction Energy Hypothesis) that has been widely used to circumvent tackling the challenging probems from (1) and (2).

Making the inaccessible accessible: Novel techniques for obtaining accurate QM/MM free energies at affordable costs

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.