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

We describe and apply a method that reduces the time taken to calculate a single binding free energy 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 (or on a high performance computer) thereby accelerating the process. We use this method to study how a series of phosphopeptides bind 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 ∆∆G 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. Running title: Calculating SH2 domain binding affinities