Recent advances in QM/MM free energy calculations using reference potentials

Abstract

BackgroundRecent 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.Scope of reviewHybrid 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.Major conclusionsThe 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.General significanceAs was already demonstrated 40 years ago, the usage of simplified models still allows one to obtain cutting edge results with substantially reduced computational cost. This article is part of a Special Issue entitled Recent developments of molecular dynamics.

Converging ligand‐binding free energies obtained with free‐energy perturbations at the quantum mechanical level

“…Another approach is to perform the sampling at the MM level and then evaluate QM/MM energies only for a restricted number of snapshots. Valid QM/MM free energies can be obtained either by a MM→QM/MM FES calculation, employing the thermodynamic cycle in Figure a, or by reweighting of the MM snapshots toward the QM/MM energy function (Figs. b and c) .…”

“…b and c) . Such approaches have been used for ligand binding, as well as for solvation free energies and quite extensively for enzyme reactions . The challenge with this approach is to obtain converged results for the MM→QM/MM perturbation, which must be performed in a single step to avoid the need of QM/MM sampling, that is, to ensure that the overlap of the MM and QM/MM potentials is large enough (a few approaches involving QM/MM sampling have been suggested).…”

“…The challenge with this approach is to obtain converged results for the MM→QM/MM perturbation, which must be performed in a single step to avoid the need of QM/MM sampling, that is, to ensure that the overlap of the MM and QM/MM potentials is large enough (a few approaches involving QM/MM sampling have been suggested). For enzyme reactions, proper convergence has been obtained by keeping the QM system fixed; without this approximation, very poor convergence has been observed, which could only partly be decreased by employing SQM/MM sampling . For binding affinities, such an approximation seems inappropriate, as the entropy and reorganisation of the ligand is expected to be important for the binding.…”

Absolute proton hydration free energy, surface potential of water, and redox potential of the hydrogen electrode from first principles: QM/MM MD free-energy simulations of sodium and potassium hydration

“…It has attracted renewed interest in recent years, 84,86 in the form of sampling approaches involving either the reweighting or perturbation of MM trajectories to the QM/MM level [185][186][187][188][189][190][191][192][193][194] (including the so-called paradynamics [195][196][197][198] or the continuous switching between MM and QM/MM interactions. 199 The advantage of adjusting the parameters of the MM model to improve the convergence has also been noted in this context.…”

Editorial preface

“…The method is validated with suitable benchmarks and its efficiency demonstrated. Kamerlin et al [10] review the concept of QM/MM free energy calculations using reference potentials. The idea behind this approach is that a lower-level potential energy description, that allows extensive sampling and free energy calculations to be carried out, is used to obtain higher-level QM or QM/MM free energies as a perturbation to the reference potential.…”