Biochem. Abstract
Abstract
The complementary spatial relationship between fullerene
C60 and the
hydrophobic cavity region of the Human Immunodeficiency Virus (HIV)
Protease, which houses
the active site of the enzyme, has lead to the
suggestion that fullerene-based derivatives could have potential use
as effective HIV protease inhibitors. The ability of such compounds to
desolvate the cavity region leads to a strong hydrophobic interaction
between the C60
moiety and residues in the cavity region. In the present
study, the connection between the motion of the so called flexible flaps
of the cavity and favorable binding of a fullerene-based
protease inhibitor is explored using multiple time scale molecular
dynamics simulations and free
energy techniques. In addition, the effect of the interaction between
the C60 moiety and the residues in the cavity region on the
water content of the cavity is also investigated. Conformational free energy profiles
along a suitably chosen flap-opening coordinate show a considerable barrier
to flap-opening in the presence of the inhibitor while no such barrier
exists for the protease alone.
This result is interpreted in terms of a strong hydrophobic interaction
between the C60 moiety and the flexible flaps, which
cause the latter to close tightly around the inhibitor, thereby
expelling water from the cavity and leading to a favorable binding interaction.
This interpretation is rationalized by direct analysis of the water
content in the cavity in the presence and absence of the inhibitor.