The Catalytic Machinery of Protein Lysine- and DNA Methyltransferases - Synergistic Research of Molecular Dynamics Simulation and Biochemistry

Philipp Schnee

The goal of this project is to uncover the molecular mechanisms behind the substrate specificity of Protein Lysin Methyltransferases (PKMTs) and DNA methyltransferases (DNMT). These enzymes play an important role in the epigenetic regulation of cellular metabolism by methylating other proteins, histones or DNA. Thereby they heavily influence the organization of the genetic information and their misregulation is often associated with neurodegenerative diseases and cancer. To uncover the mechanisms behind the substrate specificity of this group of enzymes, a combination of molecular dynamics simulation and biochemical experiments is used. Molecular dynamics (MD) simulations of the DNMT3A R882H cancer mutant revealed that more contacts in a protein-protein interface were formed, stabilizing the interaction and changing the substrate specificity. In another study it was shown by MD simulation, that the NSD2 T1150A cancer mutation causes a change in the volume of the active site, thereby changing the number of transferred methyl groups, which could lead to a dysregulation of the epigenome. These approaches showcase how simulation science can reveal molecular mechanism in PKMTs and DNMTs.

Another part of our research focuses on predictive simulations, which guide experimental strategies and indicate promising targets for drug design. Surprisingly, it was found by MD simulation that certain PKMTs prefer their peptide substrates in a hairpin conformation. This structural feature was then validated in biochemical experiments, showing that the introduction of a hairpin to existing substrates leads to an increased activity. This could be the starting point for the discovery of PKMT inhibitor, which are highly active but also specific.


  • Schnee, M. Choudalakis, S. Weirich, M. S. Khella, H. Carvalho, J. Pleiss & A. Jeltsch (2022) Mechanistic basis of the increased methylation activity of the SETD2 protein lysine methyltransferase towards a designed super-substrate peptide. Communications Chemistry, 5, 139. doi: 10.1038/s42004-022-00753-w.
  • Schnee, S. Weirich, A. Jeltsch, Charakterisierung der Substratspezifität von Protein Methyltransferasen – Methoden und Anwendungen, BIOspektrum 03/23, DOI: 10.1007/s12268-023-1930-y
  • Mina S. Khella, P. Schnee, S. Weirich, T. Bui, A. Bröhm, P. Bashtrykov, J. Pleiss, A. Jeltsch (2023) The T1150A cancer mutant of the protein lysine dimethyltransferase NSD2 can introduce H3K36 trimethylation, J Biol Chem. 2023 Jun;299(6):104796. doi: 10.1016/j.jbc.2023.104796
  • A. Mack, M. Emperle, P. Schnee, S. Adam, J. Pleiss, P. Bashtrykov, & A. Jeltsch: (2022) Preferential interaction of DNMT3A subunits containing the R882H cancer mutation leads to dominant changes of flanking sequence effects. Journal of Molecular Biology, 15;434(7):167482. doi: 10.1016/j.jmb.2022.167482
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