A meanfield approach to the thermodynamics of a protein-solvent system with application to the oligomerization of the tumor suppressor p53

The thermodynamic stability and oligomerization status of the tumor suppres sor p53 tetramerization domain have been studied experimentally and theoret ically, A series of hydrophilic mutations at Met-340 and Leu-344 of human p 53 were designed to disrupt the hydrophobic dimer-dimer interface of the te trameric oligomerization domain of p53 (residues 325-355), Meanfield calcul ations of the free energy of the solvated mutants as a function of interdim er distance were compared with experimental data on the thermal stability a nd oligomeric state (tetramer, dimer, or equilibrium mixture of both) of ea ch mutant. The calculations predicted a decreasing stability and oligomeric state for the following amino acids at residue 340: Met (tetramer) > Ser A sp, His, Gin, > Glu, Lys (dimer), whereas the experimental results showed t he following order: Met (tetramer) > Ser > Gin > His, Lys > Asp, Glu (dimer s). For residue 344, the calculated trend was Leu (tetramer) > Ala > Arg, G in, Lys (dimer), and the experimental trend was Leu (tetramer) > Ala, Arg, Gin, Lys (dimer), The discrepancy for the lysine side chain at residue 340 is attributed to the dual nature of lysine, both hydrophobic and charged. T he incorrect prediction of stability of the mutant with Asp at residue 340 is attributed to the fact that within the meanfield approach, we use the wi ld-type backbone configuration for all mutants, but low melting temperature s suggest a softening of the ai-helices at the dimer-dimer interface. Overa ll, this initial application of meanfield theory toward a protein-solvent s ystem is encouraging for the application of the theoretical model to more c omplex systems.