Efficiently computing pathway free energies: New approaches based on chain-of-replica and Non-Boltzmann Bennett reweighting schemes

Phillip S. Hudson, Justin K. White, Fiona L. Kearns, Milan Hodoscek, Stefan Boresch, H. Lee Woodcock (Corresponding author)

Publications: Contribution to journalArticlePeer Reviewed

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. General significance: 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.
Original languageEnglish
Pages (from-to)944-953
Number of pages10
JournalBiochimica et Biophysica Acta - General Subjects
Volume1850
Issue number5
DOIs
Publication statusPublished - May 2015

Austrian Fields of Science 2012

  • 104004 Chemical biology
  • 103006 Chemical physics
  • 102009 Computer simulation

Keywords

  • Reaction path
  • Free energy
  • QM/MM
  • Potential of mean force
  • Bennett's acceptance ratio
  • BAR
  • Reweighting
  • QM-Non-Boltzmann Bennett
  • QM-NBB
  • NUDGED ELASTIC BAND
  • DENSITY-FUNCTIONAL THEORY
  • GROWING STRING METHOD
  • MONTE-CARLO DATA
  • MOLECULAR-DYNAMICS
  • RANDOM-WALK
  • PERTURBATION CALCULATIONS
  • ORTHOGONAL-SPACE
  • THERMODYNAMIC INTEGRATION
  • CONFORMATIONAL-ANALYSIS

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