Computational Study of Methionine Methylation Process Catalyzed by SETD3.

Area of Science:

• Biochemistry
• Molecular Biology
• Enzymology

Background:

• SETD3 is a methyltransferase for His73 in β-actin, crucial for actin regulation.
• SETD3 can also methylate other residues like methionine, though with lower efficiency.
• Mutations N255V and N255A in SETD3 increase methionine methylation activity but decrease histidine methylation.

Purpose of the Study:

• To investigate the mechanism behind increased SETD3 activity on methionine methylation due to mutations.
• To elucidate the structural, dynamic, and energetic factors influencing SETD3-catalyzed methionine methylation.
• To understand the impact of the N255V mutation on SETD3's catalytic activity.

Main Methods:

• Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics simulations.
• Potential of Mean Force (PMF) free energy simulations.
• Analysis of enzyme-substrate complexes and reaction pathways.

Main Results:

• Methionine methylation by wild-type SETD3 has a higher free energy barrier (approx. 10 kcal/mol) compared to histidine methylation.
• The N255V mutation in SETD3 lowers the free energy barrier for methionine methylation by approximately 1 kcal/mol.
• Simulation results align with experimental observations regarding mutation effects on enzyme activity.

Conclusions:

• The study provides atomic-level insights into the mechanism of SETD3-catalyzed methionine methylation.
• The N255V mutation enhances SETD3 activity towards methionine by reducing the free energy barrier.
• Understanding these mechanisms can inform the development of targeted enzyme modulators.