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

Abstract

Results from extensive 70 ns all-atom molecular dynamics simulations of catechol-Omethyltransferase (COMT) enzyme are reported. The simulations were performed with explicit TIP3P water and Mg 2þ 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.

Crystal structures of the Apo and Holo form of rat catechol-O-methyltransferase

“…However, the ligand recognition residues moved significantly, suggesting that ligand-binding loops alter their structure for various sizes of ligands. Recently, an MD simulation structure of rat S-COMT (Bunker et al, 2008) showed that the position of each helix and sheet determined from the crystal structure of the Apo enzyme adopted almost the same position as that of the Holo and quaternary complex structures. However, the relative position of helixes and sheets determined from a 70 ns MD simulation structure was quite different from that of Apo structure; hydrogen bond-mediated helix-helix, helix-sheet, and sheet-sheet interactions might have been broken under the energy minimization steps and loosened the overall structure.…”

Molecular Dynamics Simulations Reveal Fundamental Role of Water As Factor Determining Affinity of Binding of β-Blocker Nebivolol to β2-Adrenergic Receptor

“…Despite many pharmacological and clinical studies, we are unaware of any prior computational study of nebivolol. Related atomic-level MD simulations of ligand docking have been performed for other systems such as catechol-O-methyltransfrase 17 and prolyl oligopeptidase. 18 In this paper we combine use of both molecular docking and atomistic classical MD simulations to explore the different binding modes of srrr-and ssss-nebivolol (the least active form of the drug) in the binding site of β 2 AR.…”

Curse and Blessing of Non‐Proteinogenic Parts in Computational Enzyme Engineering

“…[13] Although RESP charges are available for nicotinamide cofactors, modern automated pipelines were found to produce reliable parameters for all major force fields. [162][163] Optimized S-adenosyl-methionine (SAM) parameters have been published for various force fields, [164][165] and PLP RESP charges are available for AMBER. [166] Parameterization of flavins requires extra care because the electron density in the central three-ring structure cannot easily be fragmented into smaller groups.…”