Use of Interaction Energies in QM/MM Free Energy Simulations

Phillip S. Hudson, H. Lee Woodcock (Corresponding author), Stefan Boresch (Corresponding author)

Publications: Contribution to journalArticlePeer Reviewed

Abstract

The use of the most accurate (i.e., QM or QM/MM) levels of theory for free energy simulations (FES) is typically not possible. Primarily, this is because the computational cost associated with the extensive configurational sampling needed for converging FES is prohibitive. To ensure the feasibility of QM-based FES, the "indirect" approach is generally taken, necessitating a free energy calculation between the MM and QM/MM potential energy surfaces. Ideally, this step is performed with standard free energy perturbation (Zwanzig's equation) as it only requires simulations be carried out at the low level of theory; however, work from several groups over the past few years has conclusively shown that Zwanzig's equation is ill-suited to this task. As such, many approximations have arisen to mitigate difficulties with Zwanzig's equation. One particularly popular notion is that the convergence of Zwanzig's equation can be improved by using interaction energy differences instead of total energy differences. Although problematic numerical fluctuations (a major problem when using Zwanzig's equation) are indeed reduced, our results and analysis demonstrate that this "interaction energy approximation" (IEA) is theoretically incorrect, and the implicit approximation invoked is spurious at best. Herein, we demonstrate this via solvation free energy calculations using IEA from two different low levels of theory to the same target high level. Results from this proof-of-concept consistently yield the wrong results, deviating by ∼1.5 kcal/mol from the rigorously obtained value.
Original languageEnglish
Pages (from-to)4632-4645
Number of pages14
JournalJournal of Chemical Theory and Computation
Volume15
Issue number8
DOIs
Publication statusPublished - Aug 2019

Austrian Fields of Science 2012

  • 104017 Physical chemistry
  • 102009 Computer simulation

Keywords

  • HYDRATION FREE-ENERGIES
  • GENERAL FORCE-FIELD
  • QUANTUM-MECHANICAL CALCULATIONS
  • NONEQUILIBRIUM WORK METHODS
  • BINDING FREE-ENERGIES
  • SOLVATION FREE-ENERGY
  • MOLECULAR-DYNAMICS
  • PERTURBATION CALCULATIONS
  • CHEMICAL-PROCESSES
  • COMPLEX MATERIALS

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