Enzymatic and Inhibition Mechanism of Human Aromatase (CYP19A1) Enzyme. A Computational Perspective from QM/MM and Classical Molecular Dynamics Simulations

The enzyme human aromatase (HA), a member of the cytochrome P450 family,
catalyses in a highly specific and peculiar manner the conversion of
estrogens to androgens. Thus, this enzyme is a relevant target for
inhibitor design for the treatment of breast cancer and currently there
are several HA inhibitors employed in clinical practice. The HA crystal
structure was solved only in 2009 and, since then, several studies have
been done to characterize a variety of its structural, dynamical and
mechanistic properties. In the last decade, the predictive power and the
accuracy of computer simulations techniques, either relying on force
field or on ``ab initio'' description of the system, has enormously
increased. This was mainly due to the development of more accurate
algorithms, which allow accelerating the time-scale accessible by
simulations techniques, and to the increase of computer power. Hence,
computer simulations can now accurately paint an atomistic picture to
the molecular mechanism of biomolecules providing also an estimate of
the kinetic and thermodynamic properties of the enzyme at increasingly
quantitative level. In this review, on the basis of selected examples
taken from our work, we summarize current active research topics
concerning HA enzyme, with a focus on computational studies. In
particular, we will illustrate current results and novel hypothesis
concerning the final (rate-determining) aromatization step promoted by
this enzyme, on how the structural/dynamics/functional properties of HA
are modulated in a membrane lipophilic environment, and finally on novel
possible (allosteric) inhibition mechanisms which may modulate estrogen
production in HA.