Herein, we describe how a novel Non-Boltzmann Bennett reweighting scheme can be combined with the indirect QM/MM FES approach to avoid expensive QM simulations. Details of this new approach (i.e., QM-NBB) are presented with particular emphasis on connecting MM and QM levels of theory. QM-NBB is then applied to a number of test cases in explicit and implicit solvent with both absolute and relative solvation free energy differences computed. Further, QM-NBB is compared critically to the standard FEP based indirect scheme and some best practices are suggested for improving methods that seek to connect MM to QM (or QM/MM) levels of theory in FES.

Affordable multiscale free energy simulations: A novel method that efficiently connects low level sampling to QM/MM via non-Boltzmann Bennett reweighting

248th National Meeting (2014)

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