  Force field and first principles molecular dynamics simulations on complexes
of pig liver esterase (pig liver isoenzymes and a mutant) and selected
substrates (1-phenyl-1-ethyl acetate, 1- phenyl-2-butylacetate,
proline-{\beta}-naphthylamide and methyl butyrate) are presented. By restrained
force field simulations the access of the substrate to the hidden active site
was probed. For a few substrates spontaneous access to the active site via a
well defined entrance channel was found. The structure of the tetrahedral
intermediate was simulated for several substrates and our previous assignment
of GLU 452 instead of GLU 336 was confirmed. It was shown that the active site
readily adapts to the embedded substrate involving a varying number of
hydrophobic residues in the neighborhood. This puts into question key-lock
models for enantioselectivity. Ab initio molecular dynamics showed that the
structures we found for the tetrahedral intermediate in force field simulations
are consistent with the presumed mechanism of ester cleavage. Product release
from the active site as final step of the enzymatic reaction revealed to be
very slow and took already more than 20ns for the smallest product, methanol.
