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

Yuan Ping Pang, Kun Xu, Jamal El Yazal, Franklyn G. Prendergast

Research output: Contribution to journalArticlepeer-review

126 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1857-1865
Number of pages9
JournalProtein Science
Issue number10
StatePublished - Nov 25 2000


  • Cancer research
  • Coordination chemistry
  • Drug research
  • Farnesyltransferase
  • Metalloproteins
  • Molecular dynamics
  • Zinc

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


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