Computational Study of Methionine Methylation Process Catalyzed by SETD3

Zhao, Yuanyuan; Deng, Hao; Rahman, Adua; Xu, Xiaodong; Qian, Ping; Guo, Hong

doi:10.1007/s12539-022-00516-0

Cited by 2 publications

(3 citation statements)

References 29 publications

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“…As is demonstrated in Figure a, the barrier from the PMF simulations becomes ∼6 kcal/mol higher (i.e., 21.8 kcal/mol vs. 15.5 kcal/mol) for the first methylation of K73 in comparison with the first methylation of H73, in agreement with the results from experiments . As was pointed out in our earlier studies, , the H73, Y312 cation−π interaction is of importance for the H73 methylation (Figures d, b), including making a contribution to transition state stabilization. The cation−π interaction is recognized as a major interaction for biological systems, − and a key component of such an interaction is believed to be the electrostatic interaction involving the C–H bond dipoles in the aromatic systems .…”

Section: Resultssupporting

confidence: 88%

“…In Figure 1d, the average reactant structure for the first methylation of K73 in wild-type SETD3 is compared with that of the H73 methylation; the r(C M •••N ε2 )-θ and r(C M •••N ε2 )-β distribution maps are plotted for the methylation involving H73 in Figure 1e. The results for the H73 methylation reported here are from the systems containing the larger QM region in which Y312 is treated by QM as well, and these results are very similar to those from the earlier study 32 with the relatively small QM regions for which Y312 was not treated by QM. The similarities in the results suggest that the simulations from the models with the smaller QM region may be sufficient for the study.…”

Section: ■ Methodssupporting

confidence: 88%

“…Hydrogen atoms in the system were added by HBUILD 31 in CHARMM. The SAM QM atoms include the −CH 2 −CH 2 −S + (Me)−CH 2 − as adopted before, 32 and additional QM atoms are those from the K73 side chain. The MM atoms are those from the rest of the system.…”

Section: ■ Methodsmentioning

confidence: 99%

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Structural and Energetic Origin of Different Product Specificities and Activities for SETD3 and Its Mutants on the Methylation of the β-Actin H73K Peptide: Insights from a QM/MM Study

Zhao

Deng

et al. 2022

J. Chem. Theory Comput.

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The methylation of the lysine residue can affect some fundamental biological processes, and specific biological effects of the methylations are often related to product specificity of methyltransferases. The question remains concerning how active-site structural features and dynamics control the activity as well as the number (1, 2, or 3) of methyl groups on methyl lysine products. SET domain containing protein 3 (SETD3) has been identified recently as the β-actin histidine73-N3 methyltransferase, and also, it has a weak methylation activity on the H73K β-actin peptide for which the target H73 residue is mutated into K73. Interestingly, the K73 methylation activity of SETD3 increases significantly as a result of the N255 → A or N255 → F/W273 → A mutation, and the N255A product specificity also differs from that of wild-type. Here, we performed QM/MM molecular dynamics and potential of mean force (PMF) simulations for SETD3 and its mutants (N255A and N255F/W273A) to study how SETD3 and its mutants could have different product specificities and activities for the K73 methylation. The PMF simulations show that the barrier for the first methylation of K73 is higher compared to the barrier of the H73 methylation in SETD3. Moreover, the second methylation of K73 has been found to have a barrier from the free energy simulation that is higher by 2.2 kcal/mol compared to the barrier of the first methyl transfer to K73, agreeing with the suggestion that SETD3 is a monomethylase. For the first, second, and third methylations of K73 in the N255A mutant, the barriers obtained from the PMF simulations for transferring the second and third methyl groups are found to be lower relative to the barrier for the first methyl transfer. Thus, N255A can be considered as a trimethyl lysine methyltransferase. In addition, for the first K73 methylation, the activities from the PMF simulations follow the order of N255F/W273A > N255A > WT, in agreement with experiments. The examination of the structural and dynamic results at the active sites provides better understanding of different product specificities and activities for the K73 methylations in SETD3 and its mutants. It is demonstrated that the existence of well-balanced interactions at the active site leading to the near attack conformation is of crucial importance for the efficient methyl transfers. Moreover, the presence of potential interactions (e.g., the C–H···O and cation−π interactions) that are strengthening at the transition state can also be important. Furthermore, the activity as well as product specificity of the K73 methylation also seems to be controlled by certain active-site water molecules which may be released to provide extra space for the addition of more methyl groups on K73.

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