title: Use of Nonequilibrium Work Methods to Compute Free Energy Differences Between Molecular Mechanical and Quantum Mechanical Representations of Molecular Systems.
abstract: Carrying out free energy simulations (FES) using quantum mechanical (QM) Hamiltonians remains an attractive, albeit elusive goal. Renewed efforts in this area have focused on using "indirect" thermodynamic cycles to connect "low level" simulation results to "high level" free energies. The main obstacle to computing converged free energy results between molecular mechanical (MM) and QM (ΔA(MM→QM)), as recently demonstrated by us and others, is differences in the so-called "stiff" degrees of freedom (e.g., bond stretching) between the respective energy surfaces. Herein, we demonstrate that this problem can be efficiently circumvented using nonequilibrium work (NEW) techniques, i.e., Jarzynski's and Crooks' equations. Initial applications of computing ΔA(NEW)(MM→QM), for blocked amino acids alanine and serine as well as to generate butane's potentials of mean force via the indirect QM/MM FES method, showed marked improvement over traditional FES approaches.
authors.affiliation: Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, CHE205, Tampa, Florida 33620-5250, United States.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Hudson
authors.affiliation: Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, CHE205, Tampa, Florida 33620-5250, United States.
authors.forename: H Lee
authors.initials: HL
authors.lastname: Woodcock
authors.affiliation: Department of Computational Biological Chemistry, Faculty of Chemistry, University of Vienna , Währingerstraße 17, A-1090 Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boresch
keywords: QM/MM; free energy simulations; nonequilibrium work techniques