Rapid, accurate, and precise calculation of relative binding affinities for the SH2 domain using a computational grid

Philip W. Fowler, Sebastien Geroult, Shantenu Jha, Gabriel Waksman, Peter V. Coveney

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

We describe and apply a method that reduces the time taken to calculate binding free energies using thermodynamic integration. This method uses a stack of grid software, which we call STIMD, that allows the scientist to easily distribute the necessary simulations around a computational grid thereby accelerating the process. We use this method to study how a series of phosphopeptides binds to the Src SH2 domain. The binding of phosphopeptides to the Src SH2 domain is described by the "two-pronged plug two-holed socket" model, and we investigate this model by reducing the length of the aliphatic side chain that engages the second of the two sockets through two successive alchemical mutations. Seven different values of ΔΔG have been calculated, and we report good agreement with experiment. We then propose an extension to this model using the insights gained from a free energy component analysis.

Original languageEnglish (US)
Pages (from-to)1193-1202
Number of pages10
JournalJournal of Chemical Theory and Computation
Volume3
Issue number3
DOIs
StatePublished - May 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Computer Science Applications
  • Physical and Theoretical Chemistry

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