Computational Study of Methionine Methylation Process Catalyzed by SETD3

The SETD3 enzyme has been identified as the methyltransferase for the His73 methylation in β -actin, and such methylation plays an important role in regulating the actin’s biochemical properties and fine­tuning the protein’s cellular roles. Further studies have demonstrated that SETD3 may be able to methylase some other residues, including lysine and methionine, that substitute His73 in the β -actin peptide. The activity of SETD3 on the Met73 peptide is low without turnover. Interestingly, it has been shown that the N255V and N255A mutations of SETD3 can increase the activity by about 3-fold for the methionine methylation, while such mutations lead to a significant reduction of k cat for the His73 methylation. The detailed mechanism that leads to such increase of the activity for the Met73 methylation as a result of the mutations has not been understood. In this work, QM/MM molecular dynamics (MD) and potential of mean force (PMF) free energy simulations are undertaken for investigating structural, dynamic, and energetic properties involving the complex of SETD3 and Met73 peptide and to study the SETD3-catalyzed methionine methylation and the effects of the N255V mutation. It is demonstrated that the free energy barrier in the case of the methionine methylation in SETD3 is about 10 kcal/mol higher than that for the histidine methylation. Moreover, the free energy barrier for the methionine methylation in the N255V mutant is about 1 kcal/mol lower than that in the wild-type enzyme. These results agree with previous experimental observation. The origin of the free-energy barrier changes as a result of the H to M substitution on the β -actin peptide and the N255V mutation of SETD3 is discussed based on the data obtained from the simulations. Graphical abstract