I. Ghosh et O. Edholm, MOLECULAR-DYNAMICS STUDY OF THE BINDING OF PHENYLALANINE STEREOISOMERS TO THERMOLYSIN, Biophysical chemistry, 50(3), 1994, pp. 237-248
The stereospecificity in binding of phenylalanine as inhibitor in the
active site of the thermolysin, has been investigated by means of mole
cular dynamics simulations using free energy integration techniques. T
he difference in the free energy of binding was found to be 2.0 +/- 1.
8 kJ/mol in favour of the D-form. This agrees with the experimental va
lue, 2.8 kJ/mol. The result was obtained using a standard empirical fo
rce field (that of GROMOS). A different force field with 30% bigger ch
arges (more like ab initio charges) was also tried. This resulted in l
ess fluctuations and a more precise binding, but in a free energy diff
erence that was clearly larger than the experimental one. The phenylal
anine backbone is located close to the zinc atom and the ring stays in
the hydrophobic pocket in both the cases. The two stereoisomers diffe
r mainly in the orientation of the backbone plane with respect to the
active site and the rotational state of the dihedral around the C-alph
a-C-beta bond.