5 research outputs found
p-CMP and p-MMP kinetic constants for MAO-B and experimental and calculated free Gibbs energy barriers.
<p>p-CMP and p-MMP kinetic constants for MAO-B and experimental and calculated free Gibbs energy barriers.</p
Non-covalent interaction (NCI) surface for binding site models in TS complexes with p-CMP and p-MMP after QM optimization.
<p>Red squares indicate hydrogen bonds (blue surfaces) and favorable van der Waals interactions (light green surfaces). a) the reactive region of p-CMP; b) p-substituent region of p-CMP, c) the reactive region of p-MMP and d) p-substituent region of p-MMP. p-CMP is depicted in cyan ball and sticks while p-MMP is depicted in yellow ball and sticks. NCI indexes isovalues range from 0.035 to -0.035 (au). p-MMP (p-methoxy-β-methylphenylethylamine); p-CMP (p-chloro-β-mehtylphenylethylamine), respectively.</p
Influence of Protonation on Substrate and Inhibitor Interactions at the Active Site of Human Monoamine Oxidase-A
Although substrate conversion mediated by human monoaminooxidase
(hMAO) has been associated with the deprotonated state of their amine
moiety, data regarding the influence of protonation on substrate binding
at the active site are scarce. Thus, in order to assess protonation
influence, steered molecular dynamics (SMD) runs were carried out.
These simulations revealed that the protonated form of the substrate
serotonin (5-HT) exhibited stronger interactions at the protein surface
compared to the neutral form. The latter displayed stronger interactions
in the active site cavity. These observations support the possible
role of the deprotonated form in substrate conversion. Multigrid docking
studies carried out to rationalize the role of 5-HT protonation in
other sites besides the active site indicated two energetically favored
docking sites for the protonated form of 5-HT on the enzyme surface.
These sites seem to be interconnected with the substrate/inhibitor
cavity, as revealed by the tunnels observed by means of CAVER program.
p<i>K</i><sub>a</sub> calculations in the surface loci pointed
to Glu<sup>327</sup>, Asp<sup>328</sup>, His<sup>488</sup>, and Asp<sup>132</sup> as candidates for a possible in situ deprotonation step.
Docking analysis of a group of inhibitors (structurally related to
substrates) showed further interactions with the same two docking
access sites. Interestingly, the protonated/deprotonated amine moiety
of almost all compounds attained different docking poses in the active
site, none of them oriented to the flavin moiety, thus producing a
more variable and less productive orientations to act as substrates.
Our results highlight the role of deprotonation in facilitating substrate
conversion and also might reflect the necessity of inhibitor molecules
to adopt specific orientations to achieve enzyme inhibition