Molecular dynamics simulations of the enzyme Catechol-O-Methyltransferase: methodological issues1

¹Presented at CMTPI 2007: Computational Methods in Toxicology and Pharmacology Integrating Internet Resources (Moscow, Russia, September 1–5, 2007).

Abstract

Results from extensive 70 ns all-atom molecular dynamics simulations of catechol-O-methyltransferase (COMT) enzyme are reported. The simulations were performed with explicit TIP3P water and Mg^2 + ions. Four different crystal structures of COMT, with and without different ligands, were used. These simulations are among the most extensive of their kind and as such served as a stability test for such simulations. On the methodological side we found that the initial energy minimization procedure may be a crucial step: particular hydrogen bonds may break, and this can initiate an irreversible loss of protein structure that becomes observable in longer time scales of the order of tens of nanoseconds. This has important implications for both molecular dynamics and quantum mechanics–molecular mechanics simulations.

¹Presented at CMTPI 2007: Computational Methods in Toxicology and Pharmacology Integrating Internet Resources (Moscow, Russia, September 1–5, 2007).

Keywords:

• catechol-O-methyltransferase
• COMT
• molecular dynamics
• hydrogen bonds
• stability
• protein dynamics

Acknowledgments

This work has been supported by Emil Aaltonen foundation (M.K.) and the Natural Sciences and Engineering Research Council of Canada (M.K.). Tomasz Róg has been supported by a Marie Curie Intra-European Fellowship 024612-Glychol. Jean-Francois St. Pierre is supported through the GALENOS program. We thank the Finnish IT Center for Science (CSC) and the Southern Ontario SharcNet grid computing facility (www.sharcnet.ca) for computer resources.

Notes

¹Presented at CMTPI 2007: Computational Methods in Toxicology and Pharmacology Integrating Internet Resources (Moscow, Russia, September 1–5, 2007).