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

Abstract

AbstractFarnesyltransferase (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. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008