Successful molecular dynamics simulation of the zinc-bound farnesyltransferase using the cationic dummy atom approach

Farnesyltransferase (FT) inhibitors can suppress tumor cell proliferation w ithout substantially interfering with normal cell growth, thus holding prom ise for cancer treatment. A structure-based approach to the design of impro ved 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 conf ormational flexibility of the enzyme is still not available. Molecular dyna mics (MD) simulations of FT can offer the requisite information, but have n ot 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 prob lems 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 cat ionic dummy atoms to impose orientational requirement fur zinc ligands. A s uccessful 1.0 ns (1.0 fs time step) MD simulation of zinc-bound FT suggests that nine conserved residues (Asn127 alpha, Gln162 alpha, Asn165 alpha, Gl n195 alpha, His248 beta, Lys294 beta. Leu295 beta, Lys353 beta, and Ser357 beta) in the active site of mammalian FT are relatively mobile. Some of the se residues might be involved in the ligand-induced active site conformatio nal rearrangement upon binding and deserve attention in screening and desig n of improved FT inhibitors for cancer chemotherapy.