MultiscaleFree Energy Simulations: An Efficient Methodfor Connecting Classical MD Simulations to QM or QM/MM Free EnergiesUsing Non-Boltzmann Bennett Reweighting Schemes

摘要

The reliability of free energy simulations (FES) is limited by two factors: (a) the need for correct sampling and (b) the accuracy of the computational method employed. Classical methods (e.g., force fields) are typically used for FES and present a myriad of challenges, with parametrization being a principle one. On the other hand, parameter-free quantum mechanical (QM) methods tend to be too computationally expensive for adequate sampling. One widely used approach is a combination of methods, where the free energy difference between the two end states is computed by, e.g., molecular mechanics (MM), and the end states are corrected by more accurate methods, such as QM or hybrid QM/MM techniques. Here we report two new approaches that significantly improve the aforementioned scheme; with a focus on how to compute corrections between, e.g., the MM and the more accurate QM calculations. First, a molecular dynamics trajectory that properly samples relevant conformational degrees of freedom is generated. Next, potential energies of each trajectory frame are generated with a QM or QM/MM Hamiltonian. Freeenergy differences are then calculated based on the QM or QM/MM energiesusing either a non-Boltzmann Bennett approach (QM-NBB) or non-Boltzmannfree energy perturbation (NB-FEP). Both approaches are applied tocalculate relative and absolute solvation free energies in explicitand implicit solvent environments. Solvation free energy differences(relative and absolute) between ethane and methanol in explicit solventare used as the initial test case for QM-NBB. Next, implicit solventmethods are employed in conjunction with both QM-NBB and NB-FEP tocompute absolute solvation free energies for 21 compounds. These compoundsrange from small molecules such as ethane and methanol to fairly large,flexible solutes, such as triacetyl glycerol. Several technical aspectswere investigated. Ultimately some best practices are suggested forimproving methods that seek to connect MM to QM (or QM/MM) levelsof theory in FES.