Structural mechanism of S-adenosyl methionine binding to catechol O-methyltransferase

PLoS One. 2011;6(8):e24287. doi: 10.1371/journal.pone.0024287. Epub 2011 Aug 31.


Methyltransferases possess a homologous domain that requires both a divalent metal cation and S-adenosyl-L-methionine (SAM) to catalyze its reactions. The kinetics of several methyltransferases has been well characterized; however, the details regarding their structural mechanisms have remained unclear to date. Using catechol O-methyltransferase (COMT) as a model, we perform discrete molecular dynamics and computational docking simulations to elucidate the initial stages of cofactor binding. We find that COMT binds SAM via an induced-fit mechanism, where SAM adopts a different docking pose in the absence of metal and substrate in comparison to the holoenzyme. Flexible modeling of the active site side-chains is essential for observing the lowest energy state in the apoenzyme; rigid docking tools are unable to recapitulate the pose unless the appropriate side-chain conformations are given a priori. From our docking results, we hypothesize that the metal reorients SAM in a conformation suitable for donating its methyl substituent to the recipient ligand. The proposed mechanism enables a general understanding of how divalent metal cations contribute to methyltransferase function.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural

MeSH terms

  • Catechol O-Methyltransferase / chemistry*
  • Catechol O-Methyltransferase / metabolism*
  • Humans
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • S-Adenosylmethionine / metabolism*


  • S-Adenosylmethionine
  • Catechol O-Methyltransferase