ยท S. Geroult, S. Virdee, and G.
Waksman
The role of water in computational and experimental
derivation of binding thermodynamics of SH2 domains
Chemical Biology and Drug Design. 67: 38-45 (2006)
We have studied the role of bound interface water
molecules on the prediction of the thermodynamics of SH2 domain binding to
tyrosyl phosphopeptides using a method based on accessible surface area buried
upon association. We studied three phosphopeptide ligands, which have been
shown by Lubman and Waksman (2003) and Davidson et al. (2002) to have similar
binding free energies but very different thermodynamic signatures. The
thermodynamic model is semi-empirical and applies to the crystal structure of
the SH2 domain bound forms. We explored all possible combinations of bound
interfacial waters. We show that the model does not predict the binding
thermodynamics of either ligand. However, we identified the empirical formula
describing the heat capacity change as the source of the problem. Indeed,
systematic exploration of heat capacity change values between 0 and -300
cal/mol.deg results in a sharp distribution of the number of
ligand/SH2/water-subset structures that provide binding thermodynamics similar
to experimental values. The heat capacity change values at which the
distributions peak are different for each peptide. This prompted us to
experimentally determine the heat capacity change for each of the peptides and
we found them to coincide with the values of the peaks. The implications of
such findings are discussed.