Free Energy Perturbation Methods with Quantum Energies

In our simulations of histone modifying enzymes, the computational approaches centered on the pseudobond ab initio quantum mechanical/molecular mechanical (QM/MM) approach. This approach consists of three major components [20,26-29] a pseudobond method for the treatment of the QM/MM boundary across covalent bonds, an efficient iterative optimization procedure which allows for the use of the ab initio QM/MM method to determine the reaction paths with a realistic enzyme environment, and a free energy perturbation method to take account... 

The centroid path integral method described above enable us to conveniently determine KIEs by directly computing the ratio of the quantum partition functions for two different isotopes through free energy perturbation (FEP) theory. The use of mass perturbation in free-particle bisection sampling scheme results in a major improvement in computation accuracy for KIE calculations such that secondary kinetic isotope effects and heavy atom isotope effects can be reliably obtained. The PI-FEP/UM method is the only practical approach to yield computed secondary KIEs sufficiently accurate to be compared with experiments. ... 

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