Computing converged free energy differences between levels of theory via nonequilibrium work methods: Challenges and opportunities

Fiona L. Kearns, Phillip S. Hudson, Henry L. Woodcock (Corresponding author), Stefan Boresch

Publications: Contribution to journalArticlePeer Reviewed

Abstract

We demonstrate that Jarzynski's equation can be used to reliably compute free energy differences between low and high level representations of systems. The need for such a calculation arises when employing the so-called “indirect” approach to free energy simulations with mixed quantum mechanical/molecular mechanical (QM/MM) Hamiltonians; a popular technique for circumventing extensive simulations involving quantum chemical computations. We have applied this methodology to several small and medium sized organic molecules, both in the gas phase and explicit solvent. Test cases include several systems for which the standard approach; that is, free energy perturbation between low and high level description, fails to converge. Finally, we identify three major areas in which the difference between low and high level representations make the calculation of ∆ A low →high difficult: bond stretching and angle bending, different preferred conformations, and the response of the MM region to the charge distribution of the QM region.

Original languageEnglish
Pages (from-to)1376-1388
Number of pages13
JournalJournal of Computational Chemistry
Volume38
Issue number16
DOIs
Publication statusPublished - 15 Jun 2017

Austrian Fields of Science 2012

  • 104022 Theoretical chemistry
  • 102009 Computer simulation

Keywords

  • QM
  • MM
  • free energy simulations
  • nonequilibrium work
  • BAR
  • QM-NBB
  • MOLECULAR-DYNAMICS SIMULATIONS
  • BENNETT REWEIGHTING SCHEMES
  • HYDRATION FREE-ENERGIES
  • SOLVATION FREE-ENERGIES
  • CARBONIC-ANHYDRASE-II
  • PARTICLE MESH EWALD
  • PERTURBATION CALCULATIONS
  • FORCE-FIELD
  • THERMODYNAMIC INTEGRATION
  • BIOLOGICAL-SYSTEMS
  • QM/MM

Cite this