Farnesyltransferase (FT) inhibitors can suppress
tumor cell proliferation without substantially interfering
with normal cell growth, thus holding promise for cancer
treatment. A structure-based approach to the design of
improved FT inhibitors relies on knowledge of the conformational
flexibility of the zinc-containing active site of FT. Although
several X-ray structures of FT have been reported, detailed
information regarding the active site conformational flexibility
of the enzyme is still not available. Molecular dynamics
(MD) simulations of FT can offer the requisite information,
but have not been applied due to a lack of effective methods
for simulating the four-ligand coordination of zinc in
proteins. Here, we report in detail the problems that occurred
in the conventional MD simulations of the zinc-bound FT
and a solution to these problems by employing a simple
method that uses cationic dummy atoms to impose orientational
requirement for zinc ligands. A successful 1.0 ns (1.0
fs time step) MD simulation of zinc-bound FT suggests that
nine conserved residues (Asn127α, Gln162α, Asn165α,
Gln195α, His248β, Lys294β, Leu295β, Lys353β,
and Ser357β) in the active site of mammalian FT are
relatively mobile. Some of these residues might be involved
in the ligand-induced active site conformational rearrangement
upon binding and deserve attention in screening and design
of improved FT inhibitors for cancer chemotherapy.
