Exploring the properties of small molecule protein binding via molecular simulations: the TRSH–p53 core domain complex

Abstract

Molecular dynamics simulations have been performed to investigate the binding of tris(hydroxymethyl)-aminomethane to the surface of the core domain of the mouse cellular tumor antigen p53 employing the GROMOS 45A4 and 53A6 force field parameter sets. A close investigation of the crystal structure reported by Ho et al. revealed that the protonated form is bound to the protein, i.e. a tris(hydroxymethyl)-methylammonium ion (TRSH). Molecular Dynamics (MD) simulations indicate that the p53 protein gains stability upon binding the ligand. In addition to MD simulations of the p53 protein with and without the TRSH compound, thermodynamic integration was utilised to estimate the free enthalpy of binding of the TRSH–p53 complex, which was estimated to be −49 and −54 kJ mol⁻¹ utilising the 45A4 and 53A6 force fields, respectively.