An efficient method for the calculation of quantum mechanics/molecular mechanics free energies

Christopher J. Woods*, Frederick R. Manby, Adrian J. Mulholland

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

77 Citations (Scopus)

Abstract

The combination of quantum mechanics (QM) with molecular mechanics (MM) offers a route to improved accuracy in the study of biological systems, and there is now significant research effort being spent to develop QM/MM methods that can be applied to the calculation of relative free energies. Currently, the computational expense of the QM part of the calculation means that there is no single method that achieves both efficiency and rigor; either the QM/MM free energy method is rigorous and computationally expensive, or the method introduces efficiency-led assumptions that can lead to errors in the result, or a lack of generality of application. In this paper we demonstrate a combined approach to form a single, efficient, and, in principle, exact QM/MM free energy method. We demonstrate the application of this method by using it to explore the difference in hydration of water and methane. We demonstrate that it is possible to calculate highly converged QM/MM relative free energies at the MP2/aug-cc-pVDZ/OPLS level within just two days of computation, using commodity processors, and show how the method allows consistent, high-quality sampling of complex solvent configurational change, both when perturbing hydrophilic water into hydrophobic methane, and also when moving from a MM Hamiltonian to a QM/MM Hamiltonian. The results demonstrate the validity and power of this methodology, and raise important questions regarding the compatibility of MM and QM/MM forcefields, and offer a potential route to improved compatibility. (c) 2008 American Institute of Physics.

Translated title of the contributionAn Efficient Method for the Calculation of QM/MM Free Energies
Original languageEnglish
Article number014109
Pages (from-to)1 - 8
Number of pages8
JournalJournal of Chemical Physics
Volume128
Issue number1
DOIs
Publication statusPublished - 7 Jan 2008

Keywords

  • AB-INITIO QM/MM
  • COMPUTER-SIMULATIONS
  • POTENTIAL FUNCTIONS
  • LIQUID WATER
  • ENZYMATIC-REACTIONS
  • THROMBIN INHIBITION
  • BIOMOLECULAR SYSTEMS
  • MONTE-CARLO SIMULATIONS
  • BINDING FREE-ENERGIES
  • REPLICA-EXCHANGE METHOD

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