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

      * , , , *

      Biochimica et Biophysica Acta

      Elsevier Pub. Co

      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

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          Abstract

          Background

          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.

          Scope of review

          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.

          Major conclusions

          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.

          General significance

          As 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.

          Highlights

          • We present some of the advances to accelerate high-level QM/MM calculations.
          • Quantitative limitations of low-level methods can be overcome by these approaches.
          • Reference potentials make free energy simulations feasible for large systems.
          • Automated fitting reduces the need of expensive sampling of high-level approaches.
          • Application of reference potentials can be extended to a wide range of processes.

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          Most cited references 192

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          Statistical Mechanics of Fluid Mixtures

           John Kirkwood (1935)
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            Insights into current limitations of density functional theory.

            Density functional theory of electronic structure is widely and successfully applied in simulations throughout engineering and sciences. However, for many predicted properties, there are spectacular failures that can be traced to the delocalization error and static correlation error of commonly used approximations. These errors can be characterized and understood through the perspective of fractional charges and fractional spins introduced recently. Reducing these errors will open new frontiers for applications of density functional theory.
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              Linear scaling electronic structure methods

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                Author and article information

                Affiliations
                Science for Life Laboratory, Department of Cell and Molecular Biology (ICM), Uppsala University, BMC Box 596, S-751 24 Uppsala, Sweden
                Author notes
                Contributors
                Journal
                Biochim Biophys Acta
                Biochim. Biophys. Acta
                Biochimica et Biophysica Acta
                Elsevier Pub. Co
                0006-3002
                1 May 2015
                May 2015
                : 1850
                : 5
                : 954-965
                25038480 4547088 S0304-4165(14)00246-3 10.1016/j.bbagen.2014.07.008
                © 2014 The Authors. Published by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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