Use of Nonequilibrium Work Methods to Compute Free Energy Differences Between Molecular Mechanical and Quantum Mechanical Representations of Molecular Systems

Carrying out free energy simulations (FES) using quantum mechanical (QM) Harniltonians 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 (Delta A(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 Delta A(NEW)(MM -> QM), for blocked amino acids alanine and serine as well as to generate butane's potentials indirect QM/MM FES method, showed marked improvement over traditional FES approaches.