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

• Published in: Biochimica et biophysica acta Vol. 1850; no. 5; pp. 954 - 965
• Main Authors: Duarte, Fernanda, Amrein, Beat A., Blaha-Nelson, David, Kamerlin, Shina C.L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2015; Elsevier Pub. Co
• Subjects: Averaging potential; Chlorides - chemistry; cost effectiveness; Energy Transfer; Ethylene Dichlorides - chemistry; Gibbs free energy; Hydrolases - chemistry; Kinetics; Mean field approximation; Methyl Chloride - chemistry; molecular dynamics; Molecular Dynamics Simulation - standards; Multiscale modeling; Protein Conformation; Protein Folding; Protein Stability; Protein Unfolding; Proteins - chemistry; QM/MM free energy calculation; Reference potential; Reference Standards; Review; Structure-Activity Relationship; Surface Properties; Thermodynamics; Uracil - chemistry; RS; Mean field approximation; CG; ABF; PMF; QM/MM; REMD; Multiscale modeling; EVB; FEP; PD; QTCP; MD; Reference potential; LRA; Averaging potential; SCC-DFTB; QM/MM free energy calculation; US; TS
• ISSN: 0304-4165; 0006-3002; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2014.07.008

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. As was already demonstrated 40years 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. •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.