Influence of protonation on substrate and inhibitor interactions at the active site of human monoamine oxidase-A

Gerald Zapata-Torres, Angelica Fierro, Sebastian Miranda-Rojas, Carlos Guajardo, Patricio Saez-Briones, J. Cristian Salgado, Cristian Celis-Barros

Resultado de la investigación: Article

9 Citas (Scopus)

Resumen

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. pK a calculations in the surface loci pointed to Glu 327, Asp 328, His 488, and Asp 132 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.

Idioma originalEnglish
Páginas (desde-hasta)1213-1221
Número de páginas9
PublicaciónJournal of Chemical Information and Modeling
Volumen52
N.º5
DOI
EstadoPublished - 25 may 2012

Huella dactilar

Protonation
Substrates
interaction
Serotonin
Deprotonation
candidacy
Amines
simulation
Enzyme inhibition
human monoamine oxidase A
Oxidoreductases
Group
Molecular dynamics
Tunnels
Membrane Proteins
Enzymes
Proteins
Molecules

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Citar esto

Zapata-Torres, Gerald ; Fierro, Angelica ; Miranda-Rojas, Sebastian ; Guajardo, Carlos ; Saez-Briones, Patricio ; Salgado, J. Cristian ; Celis-Barros, Cristian. / Influence of protonation on substrate and inhibitor interactions at the active site of human monoamine oxidase-A. En: Journal of Chemical Information and Modeling. 2012 ; Vol. 52, N.º 5. pp. 1213-1221.
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abstract = "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. pK a calculations in the surface loci pointed to Glu 327, Asp 328, His 488, and Asp 132 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.",
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Influence of protonation on substrate and inhibitor interactions at the active site of human monoamine oxidase-A. / Zapata-Torres, Gerald; Fierro, Angelica; Miranda-Rojas, Sebastian; Guajardo, Carlos; Saez-Briones, Patricio; Salgado, J. Cristian; Celis-Barros, Cristian.

En: Journal of Chemical Information and Modeling, Vol. 52, N.º 5, 25.05.2012, p. 1213-1221.

Resultado de la investigación: Article

TY - JOUR

T1 - Influence of protonation on substrate and inhibitor interactions at the active site of human monoamine oxidase-A

AU - Zapata-Torres, Gerald

AU - Fierro, Angelica

AU - Miranda-Rojas, Sebastian

AU - Guajardo, Carlos

AU - Saez-Briones, Patricio

AU - Salgado, J. Cristian

AU - Celis-Barros, Cristian

PY - 2012/5/25

Y1 - 2012/5/25

N2 - 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. pK a calculations in the surface loci pointed to Glu 327, Asp 328, His 488, and Asp 132 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.

AB - 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. pK a calculations in the surface loci pointed to Glu 327, Asp 328, His 488, and Asp 132 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.

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DO - 10.1021/ci300081w

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SN - 1549-9596

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