Thermolysin binding free energy

Bash et al. (1987) applied the thermodynamic perturbation method to complexes of thermolysin with a phosphonamidate [Cbz-Gly -(NH)-Leu-Leu] and the corresponding phosphonate inhibitor [Cbz-Gly -(0)-Leu-Leu]. The perturbation was carried out by using 20 windows, with 2-psec molecular dynamics simulations in each window. Computations were for the ligand in solution and bound to the enzyme. The solvation of the enzyme was represented by a spherical cap of 168 water molecules about the bound inhibitor. The difference in free energy of binding of the two inhibitors was calculated to be 4.38 kcal/mol, to be compared with the experimental value, 4.10 kcal/mol. These calculations point out the importance of solvation effects, which are seen in the 3.4 kcal/mol difference between the NH and O forms of the inhibitor. 

Wong and McCammon (120) described the calculation of the free-energy difference of binding benzamidine versus para-fluorobenzamidine to trypsin, while Bash et al. (121) reported calculations on free energy of binding differences for several thermolysin inhibitors and for a single thermolysin inhibitor to different mutant thermolysins. Merz and Kollman (122) recently... 

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