Molecular dynamics simulations of the enzyme catechol-O-methyltransferase: methodological issues.

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 Mg2+ 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.

Effects of histamine H(3)-ligands on the levodopa-induced turning behavior of hemiparkinsonian rats.

Histamine H(3)-receptors act as heteroreceptors on many neurons. The effects of H(3)-ligands (an agonist, R-alpha-methylhistamine and an antagonist, thioperamide) on levodopa-induced turning behavior in a rat model of Parkinson's disease were quite similar to those seen with alpha(2)-adrenoceptor ligands (dexmedetomidine and atipamezole). R-alpha-methylhistamine clearly reduced contralateral turning behavior but the increase of turning behavior after thioperamide was less clear. The lack of effect of H(3)-ligands, in contrast to alpha(2)-ligands, on the amphetamine-induced ipsilateral turning behavior points to different roles or neuronal distribution of these two presynaptic receptors. We propose that in this lesion model, H(3)-receptors modify those pathways participating striatal outflow.