title: Computing converged free energy differences between levels of theory via nonequilibrium work methods: Challenges and opportunities.
abstract: We demonstrate that Jarzynski's equation can be used to reliably compute free energy differences between low and high level representations of systems. The need for such a calculation arises when employing the so-called "indirect" approach to free energy simulations with mixed quantum mechanical/molecular mechanical (QM/MM) Hamiltonians; a popular technique for circumventing extensive simulations involving quantum chemical computations. We have applied this methodology to several small and medium sized organic molecules, both in the gas phase and explicit solvent. Test cases include several systems for which the standard approach; that is, free energy perturbation between low and high level description, fails to converge. Finally, we identify three major areas in which the difference between low and high level representations make the calculation of ΔAlow→high difficult: bond stretching and angle bending, different preferred conformations, and the response of the MM region to the charge distribution of the QM region. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave, CHE205, Tampa, Florida, 33620-5250.
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Kearns
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave, CHE205, Tampa, Florida, 33620-5250.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Hudson
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave, CHE205, Tampa, Florida, 33620-5250.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Woodcock
authors.affiliation: Faculty of Chemistry, Department of Computational Biological Chemistry, University of Vienna, Währingerstraße 17, Vienna, A-1090, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boresch
keywords: BAR; QM-NBB; QM/MM; free energy simulations; nonequilibrium work