· S. Geroult, M. Hooda, S. Virdee, and G.
Waksman.
Prediction of solvation sites at the interface of Src SH2 domain complexes
using molecular dynamics simulations
Chemical Biology and Drug Design. 70:87-99
(2007).
Src Homology 2 (SH2) domains are ~100 amino acid domains that
mediate recognition of tyrosine-phosphorylated sites by signalling proteins.
Structures of SH2 domains with bound ligands indicate a potentially important
role of water in influencing the binding thermodynamics. In this study, we used
molecular dynamics (MD) simulation methods to evaluate solvation sites at the
binding interface of the Src SH2 domain. We designed a software, WaRP (Water
Residency Potential), to compute the positions of hydration sites from
coordinates data of MD simulations and studied the impact of the computed
positions on the prediction of the thermodynamics of Src SH2 domain binding to
phosphorylated peptides using a method based on accessible surface area buried
upon association. Two dually phosphorylated ligands and one mono phosphorylated
ligand were studied. We showed that the software predicted between 70 and 85%
of the crystallographic water molecules depending on complexes. Comparison of
the predicted water structures of both the bound and unbound binding partners
led to a thorough evaluation of water behaviour during the binding reaction. We
also showed that the predicted water structures of all ligand-SH2 domain
structures investigated may be used to derive the entropy change provided that
the heat capacity change is known. This study is the first to examine the
dynamics of the water structure around the SH2 domain binding interface and
contributes to our understanding of binding thermodynamics in SH2 domains.