The zinc-containing enzyme HDAC-like amidohydrolase
(FB188 HDAH), identified in the Bordetella
alcaligenesbacteria, is similar to enzymes that participate in epigenetic mechanisms
such as histone modifications. The X-ray crystal structure of FB188 HDAH complexed
with the antagonist SAHA (suberoylanilide hydroxamic acid) has been solved (PDB
ID: 1ZZ1). Notably, the complex crystallizes as a tetramer in the asymmetric
unit cell of the crystal. The crystal yielded a suitable structure to analyze
the dynamics of the inhibitory mechanism of SAHA on this histone deacetylase.
Applying computational chemistry techniques and quantum mechanics theory,
several physicochemical properties were calculated to compare the active site
of the enzyme of the four monomers. Significant differences were observed in
the areas and volumes of the binding pocket, as well as hydrophobic
interactions, dipole moments, atomic charges and electrostatic potential, among
other properties. Remarkably, a free-energy curve resulting from the evaluation
of the energies of SAHA and the interacting amino acids of the four crystal
monomers unveiled the biophysical mechanism of the FB188 HDAH inhibition
exerted by SAHA to a greater extent. The biophysical mechanism of SAHA
inhibition on FB188 deacetylase was clearly observed as a dynamic process. It
is possible to define the physicochemical dynamics of the molecular complex by
the application of computational chemistry techniques and quantum mechanics
theory by studying the crystal structures of the interacting molecules.
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