Molecular dynamics analysis of farnesyltransferase: A closer look into the amino acid behavior

摘要

Farnesyltransferase (FTase) is a zinc enzyme that catalyzes the addition of a 15 carbons isoprenoid group from farnesyl diphosphate to protein substrates containing a typical -CAAX motif, where C is a cysteine residue. Among the possible CAAX substrates for FTase are a large number of biologically relevant proteins involved in cancer development, including the Ras family of proteins. FTase thus quickly became a very promising target for anticancer therapy, despite the fact that a number of questions regarding its catalytic activity have remained unexplained. This study describes the successful application of three sets of molecular dynamics parameters specifically designed to allow a reliable treatment of the zinc coordination sphere in the four key intermediate states formed during the catalytic cycle of this enzyme-FTase resting state, binary complex (FTase-FPP), ternary complex (FTase-FPP-CAAX), and product complex-allowing a detailed analysis of the dynamic behavior of the several amino acid residues that constitute the enzyme, and complementing the more rigid time-averaged snapshot-view given by the available X-crystallographic structures with a more global structural vision that takes motion into account. (c) 2008 Wiley Periodicals, Inc.