title: Recent advances in QM/MM free energy calculations using reference potentials.
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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology (ICM), Uppsala University, BMC Box 596, S-751 24 Uppsala, Sweden. Electronic address: fernanda.duarte@icm.uu.se.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Duarte
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology (ICM), Uppsala University, BMC Box 596, S-751 24 Uppsala, Sweden.
authors.forename: Beat A
authors.initials: BA
authors.lastname: Amrein
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology (ICM), Uppsala University, BMC Box 596, S-751 24 Uppsala, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Blaha-Nelson
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology (ICM), Uppsala University, BMC Box 596, S-751 24 Uppsala, Sweden. Electronic address: kamerlin@icm.uu.se.
authors.forename: Shina C L
authors.initials: SCL
authors.lastname: Kamerlin
mesh_terms: D002712:Chlorides / Q000737:chemistry; D004735:Energy Transfer; D005025:Ethylene Dichlorides / Q000737:chemistry; D006867:Hydrolases / Q000737:chemistry; D007700:Kinetics; D008737:Methyl Chloride / Q000737:chemistry; D056004:Molecular Dynamics Simulation / Q000592:standards; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability; D058767:Protein Unfolding; D011506:Proteins / Q000737:chemistry*; D012015:Reference Standards; D013329:Structure-Activity Relationship; D013499:Surface Properties; D013816:Thermodynamics; D014498:Uracil / Q000737:chemistry
chemical_list: D002712:Chlorides; D005025:Ethylene Dichlorides; D011506:Proteins; D014498:Uracil; D008737:Methyl Chloride; D006867:Hydrolases; C046137:haloalkane dehalogenase
keywords: Averaging potential; Mean field approximation; Multiscale modeling; QM/MM free energy calculation; Reference potential