title: QM/MM free energy simulations: recent progress and challenges.
abstract: Due to the higher computational cost relative to pure molecular mechanical (MM) simulations, hybrid quantum mechanical/molecular mechanical (QM/MM) free energy simulations particularly require a careful consideration of balancing computational cost and accuracy. Here we review several recent developments in free energy methods most relevant to QM/MM simulations and discuss several topics motivated by these developments using simple but informative examples that involve processes in water. For chemical reactions, we highlight the value of invoking enhanced sampling technique (e.g., replica-exchange) in umbrella sampling calculations and the value of including collective environmental variables (e.g., hydration level) in metadynamics simulations; we also illustrate the sensitivity of string calculations, especially free energy along the path, to various parameters in the computation. Alchemical free energy simulations with a specific thermodynamic cycle are used to probe the effect of including the first solvation shell into the QM region when computing solvation free energies. For cases where high-level QM/MM potential functions are needed, we analyze two different approaches: the QM/MM-MFEP method of Yang and co-workers and perturbative correction to low-level QM/MM free energy results. For the examples analyzed here, both approaches seem productive although care needs to be exercised when analyzing the perturbative corrections.
authors: Department of Chemistry and Theoretical Chemistry Institute, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA.
authors: Xiya
authors: X
authors: Lu
authors: Department of Chemistry and Theoretical Chemistry Institute, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA.
authors: Dong
authors: D
authors: Fang
authors: Department of Physics, Graduate School of Science, Nagoya University, Nagoya, Aichi 464-8602, Japan.
authors: Shingo
authors: S
authors: Ito
authors: Department of Physics, Graduate School of Science, Nagoya University, Nagoya, Aichi 464-8602, Japan.
authors: Yuko
authors: Y
authors: Okamoto
authors: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Boston, MA 02138.
authors: Victor
authors: V
authors: Ovchinnikov
authors: Department of Chemistry and Theoretical Chemistry Institute, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA.
authors: Qiang
authors: Q
authors: Cui