title: Efficiently computing pathway free energies: New approaches based on chain-of-replica and Non-Boltzmann Bennett reweighting schemes.
abstract: BACKGROUND
  Accurately modeling condensed phase processes is one of computation's most difficult challenges. Include the possibility that conformational dynamics may be coupled to chemical reactions, where multiscale (i.e., QM/MM) methods are needed, and this task becomes even more daunting.
  
  
  METHODS
  Free energy simulations (i.e., molecular dynamics), multiscale modeling, and reweighting schemes.
  
  
  RESULTS
  Herein, we present two new approaches for mitigating the aforementioned challenges. The first is a new chain-of-replica method (off-path simulations, OPS) for computing potentials of mean force (PMFs) along an easily defined reaction coordinate. This development is coupled with a new distributed, highly-parallel replica framework (REPDstr) within the CHARMM package. Validation of these new schemes is carried out on two processes that undergo conformational changes. First is the simple torsional rotation of butane, while a much more challenging glycosidic rotation (in vacuo and solvated) is the second. Additionally, a new approach that greatly improves (i.e., possibly an order of magnitude) the efficiency of computing QM/MM PMFs is introduced and compared to standard schemes. Our efforts are grounded in the recently developed method for efficiently computing QM-based free energies (i.e., QM-Non-Boltzmann Bennett, QM-NBB). Again, we validate this new technique by computing the QM/MM PMF of butane's torsional rotation.
  
  
  CONCLUSIONS
  The OPS-REPDstr method is a promising new approach that overcomes many limitations of standard pathway simulations in CHARMM. The combination of QM-NBB with pathway techniques is very promising as it offers significant advantages over current procedures.
  
  
  CONCLUSIONS
  Efficiently computing potentials of mean force is a major, unresolved, area of interest. This article is part of a Special Issue entitled Recent developments of molecular dynamics.
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., CHE205, Tampa, FL 33620-5250, USA.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Hudson
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., CHE205, Tampa, FL 33620-5250, USA.
authors.forename: Justin K
authors.initials: JK
authors.lastname: White
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., CHE205, Tampa, FL 33620-5250, USA.
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Kearns
authors.affiliation: Center for Molecular Modeling, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
authors.forename: Milan
authors.initials: M
authors.lastname: Hodoscek
authors.affiliation: Department of Computational Biological Chemistry, Faculty of Chemistry, University of Vienna, Währingerstraße 17, A-1090 Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boresch
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., CHE205, Tampa, FL 33620-5250, USA. Electronic address: hlw@usf.edu.
authors.forename: H
authors.initials: H
authors.lastname: Lee Woodcock
mesh_terms: D000465:Algorithms; D002073:Butanes / Q000737:chemistry; D002236:Carbohydrate Conformation; D004735:Energy Transfer; D008320:Maltose / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D015203:Reproducibility of Results; D012399:Rotation; D012997:Solvents / Q000737:chemistry; D054159:Torsion, Mechanical
chemical_list: D002073:Butanes; D012997:Solvents; D008320:Maltose; C046888:butane
keywords: BAR; Bennett's acceptance ratio; Free energy; Potential of mean force; QM-NBB; QM-Non-Boltzmann Bennett; QM/MM; Reaction path; Reweighting