1 May 2015
ABF, adaptive biasing force, CG, coarse-grained, EVB, empirical valence bond, FEP, free energy perturbation, LRA, linear response approximation, MD, molecular dynamics, PD, paradynamics, PMF, potential of mean force, QM/MM, quantum mechanics/molecular mechanics, QTCP, QM/MM thermodynamic cycle perturbation, US, umbrella sampling, REMD, replica exchange molecular dynamics, RS, reactant state, SCC-DFTB, self-consistent charge density functional tight binding, TS, transition state, Multiscale modeling, QM/MM free energy calculation, Averaging potential, Reference potential, Mean field approximation
Recent years have seen enormous progress in the development of methods for modeling (bio)molecular systems. This has allowed for the simulation of ever larger and more complex systems. However, as such complexity increases, the requirements needed for these models to be accurate and physically meaningful become more and more difficult to fulfill. The use of simplified models to describe complex biological systems has long been shown to be an effective way to overcome some of the limitations associated with this computational cost in a rational way.
Hybrid QM/MM approaches have rapidly become one of the most popular computational tools for studying chemical reactivity in biomolecular systems. However, the high cost involved in performing high-level QM calculations has limited the applicability of these approaches when calculating free energies of chemical processes. In this review, we present some of the advances in using reference potentials and mean field approximations to accelerate high-level QM/MM calculations. We present illustrative applications of these approaches and discuss challenges and future perspectives for the field.
The use of physically-based simplifications has shown to effectively reduce the cost of high-level QM/MM calculations. In particular, lower-level reference potentials enable one to reduce the cost of expensive free energy calculations, thus expanding the scope of problems that can be addressed.