The Importance of the Role of Lysine 16 and GAP on the Molecular Switching Mechanism of Ras Protein p21

Abstract

Molecular switching mechanism of Ras protein p21 which plays an important role for the intracellular signaling cascades was studied by using semiempirical MO method (PM3 method). A conclusion of this study is that the role of Lys16 is most important in the GTPase activity of Ras p21. The mechanism of this GTPase is as follows: in the signal-on state of Ras p21, a H₃O molecule coordinates with the phosphorus atom of γ-phosphate and forms a hydrogen bond with the oxygen atom of γ-phosphate which have already produced another hydrogen bond with a nitrogen atom of Lys16 (Nζ atom). There is the third hydrogen bond between this Nζ atom and an oxygen atom of β-phosphate. Subsequently a proton relay reaction occurs among these three hydrogen bonds and a bond cleavage between γ- and β-phosphates is generated to produce GDP. As the result, the signal-off state appears. Potential energy in ratedetermining step of this hydrolysis reaction from GTP to (GDP + P) was calculated to be 26.81 kcal/mol.