Grid-based steered thermodynamic integration accelerates the calculation of binding free energies

Philip W. Fowler, Shantenu Jha, Peter V. Coveney

Research output: Contribution to journalReview articlepeer-review

25 Scopus citations

Abstract

The calculation of binding free energies is important in many condensed matter problems. Although formally exact computational methods have the potential to complement, add to, and even compete with experimental approaches, they are difficult to use and extremely time consuming. We describe a Grid-based approach for the calculation of relative binding free energies, which we call Steered Thermodynamic Integration calculations using Molecular Dynamics (STIMD), and its application to Src homology 2 (SH2) protein cell signalling domains. We show that the time taken to compute free energy differences using thermodynamic integration can be significantly reduced: potentially from weeks or months to days of wall-clock time. To be able to perform such accelerated calculations requires the ability to both run concurrently and control in realtime several parallel simulations on a computational Grid. We describe how the RealityGrid computational steering system, in conjunction with a scalable classical MD code, can be used to dramatically reduce the time to achieve a result. This is necessary to improve the adoption of this technique and further allows more detailed investigations into the accuracy and precision of thermodynamic integration. Initial results for the Src SH2 system are presented and compared to a reported experimental value. Finally, we discuss the significance of our approach.

Original languageEnglish (US)
Pages (from-to)1999-2015
Number of pages17
JournalPhilosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences
Volume363
Issue number1833
DOIs
StatePublished - Aug 15 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Mathematics
  • General Engineering
  • General Physics and Astronomy

Keywords

  • Computational steering
  • Free energy
  • Grid computing
  • Molecular dynamics
  • Src homology 2 domains
  • Thermodynamic integration

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