title: Rapid, Accurate, and Precise Calculation of Relative Binding Affinities for the SH2 Domain Using a Computational Grid.
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.
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K., School of Crystallography, Birkbeck College, University of London, Malet Street, London WC1E 7HX, U.K., and Department of Biochemistry & Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Fowler
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K., School of Crystallography, Birkbeck College, University of London, Malet Street, London WC1E 7HX, U.K., and Department of Biochemistry & Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Geroult
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K., School of Crystallography, Birkbeck College, University of London, Malet Street, London WC1E 7HX, U.K., and Department of Biochemistry & Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
authors.forename: Shantenu
authors.initials: S
authors.lastname: Jha
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K., School of Crystallography, Birkbeck College, University of London, Malet Street, London WC1E 7HX, U.K., and Department of Biochemistry & Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Waksman
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K., School of Crystallography, Birkbeck College, University of London, Malet Street, London WC1E 7HX, U.K., and Department of Biochemistry & Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Coveney