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Computational study of a model system of enzyme-mediated [4+2] cycloaddition reaction.

Gordeev EG, Ananikov VP - PLoS ONE (2015)

Bottom Line: A possible mechanistic pathway related to an enzyme-catalyzed [4+2] cycloaddition reaction was studied by theoretical calculations at density functional (B3LYP, O3LYP, M062X) and semiempirical levels (PM6-DH2, PM6) performed on a model system.The calculations were carried out for the key [4+2] cycloaddition step considering enzyme-catalyzed biosynthesis of Spinosyn A in a model reaction, where a reliable example of a biological Diels-Alder reaction was reported experimentally.Modeling of such a system with coordination of three amino acids indicated a reliable decrease of activation energy by ~18.0 kcal/mol as compared to a non-catalytic transformation.

View Article: PubMed Central - PubMed

Affiliation: Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospekt 47, Moscow, Russia.

ABSTRACT
A possible mechanistic pathway related to an enzyme-catalyzed [4+2] cycloaddition reaction was studied by theoretical calculations at density functional (B3LYP, O3LYP, M062X) and semiempirical levels (PM6-DH2, PM6) performed on a model system. The calculations were carried out for the key [4+2] cycloaddition step considering enzyme-catalyzed biosynthesis of Spinosyn A in a model reaction, where a reliable example of a biological Diels-Alder reaction was reported experimentally. In the present study it was demonstrated that the [4+2] cycloaddition reaction may benefit from moving along the energetically balanced reaction coordinate, which enabled the catalytic rate enhancement of the [4+2] cycloaddition pathway involving a single transition state. Modeling of such a system with coordination of three amino acids indicated a reliable decrease of activation energy by ~18.0 kcal/mol as compared to a non-catalytic transformation.

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Comparison of regular and proposed cycloaddition reactions.Comparison of regular (black line) and proposed in the present study (blue line) cycloaddition reactions (calculated at the PM6 level). Coordination of amino acids and schematic substrate transformations are shown in the case of enzyme-catalyzed reaction (See S9 Fig and S10 Fig for structures and geometries).
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pone.0119984.g003: Comparison of regular and proposed cycloaddition reactions.Comparison of regular (black line) and proposed in the present study (blue line) cycloaddition reactions (calculated at the PM6 level). Coordination of amino acids and schematic substrate transformations are shown in the case of enzyme-catalyzed reaction (See S9 Fig and S10 Fig for structures and geometries).

Mentions: In the studied system this kind of transformation may start with initial state I, where substrate 1 is located in a hydrophobic environment of the enzyme (Fig. 3). For the substrate bond distances C7-C11 = 3.217 Å and C4-C12 = 3.952 Å were calculated at the starting point (see Fig. 2 for atom numbering). A coordination of the substrate with an amino acid residue initiates an arrangement of the enzyme active center and H-bond formation with C9-OH was calculated to be exothermic by 7.3 kcal/mol (II; Fig. 3) (we have selected Gln and Ser for the model computational study as these amino acids were shown to be involved in the active center of enzymes with cycloaddition activity (see refs. [35, 36]) and the choice of these amino acids is not strictly limited, since coordination of other amino acids would lead to a similar energy gain). Upon moving in the enzyme active center the substrate experienced the influence of the protein environment and returned to the thermoneutral state on the calculated energy surface (III) after contraction of the macrocycle resulted in a shortening of the C7-C11 and C4-C12 bonds to 2.619 Å and 2.830 Å, respectively.


Computational study of a model system of enzyme-mediated [4+2] cycloaddition reaction.

Gordeev EG, Ananikov VP - PLoS ONE (2015)

Comparison of regular and proposed cycloaddition reactions.Comparison of regular (black line) and proposed in the present study (blue line) cycloaddition reactions (calculated at the PM6 level). Coordination of amino acids and schematic substrate transformations are shown in the case of enzyme-catalyzed reaction (See S9 Fig and S10 Fig for structures and geometries).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390235&req=5

pone.0119984.g003: Comparison of regular and proposed cycloaddition reactions.Comparison of regular (black line) and proposed in the present study (blue line) cycloaddition reactions (calculated at the PM6 level). Coordination of amino acids and schematic substrate transformations are shown in the case of enzyme-catalyzed reaction (See S9 Fig and S10 Fig for structures and geometries).
Mentions: In the studied system this kind of transformation may start with initial state I, where substrate 1 is located in a hydrophobic environment of the enzyme (Fig. 3). For the substrate bond distances C7-C11 = 3.217 Å and C4-C12 = 3.952 Å were calculated at the starting point (see Fig. 2 for atom numbering). A coordination of the substrate with an amino acid residue initiates an arrangement of the enzyme active center and H-bond formation with C9-OH was calculated to be exothermic by 7.3 kcal/mol (II; Fig. 3) (we have selected Gln and Ser for the model computational study as these amino acids were shown to be involved in the active center of enzymes with cycloaddition activity (see refs. [35, 36]) and the choice of these amino acids is not strictly limited, since coordination of other amino acids would lead to a similar energy gain). Upon moving in the enzyme active center the substrate experienced the influence of the protein environment and returned to the thermoneutral state on the calculated energy surface (III) after contraction of the macrocycle resulted in a shortening of the C7-C11 and C4-C12 bonds to 2.619 Å and 2.830 Å, respectively.

Bottom Line: A possible mechanistic pathway related to an enzyme-catalyzed [4+2] cycloaddition reaction was studied by theoretical calculations at density functional (B3LYP, O3LYP, M062X) and semiempirical levels (PM6-DH2, PM6) performed on a model system.The calculations were carried out for the key [4+2] cycloaddition step considering enzyme-catalyzed biosynthesis of Spinosyn A in a model reaction, where a reliable example of a biological Diels-Alder reaction was reported experimentally.Modeling of such a system with coordination of three amino acids indicated a reliable decrease of activation energy by ~18.0 kcal/mol as compared to a non-catalytic transformation.

View Article: PubMed Central - PubMed

Affiliation: Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospekt 47, Moscow, Russia.

ABSTRACT
A possible mechanistic pathway related to an enzyme-catalyzed [4+2] cycloaddition reaction was studied by theoretical calculations at density functional (B3LYP, O3LYP, M062X) and semiempirical levels (PM6-DH2, PM6) performed on a model system. The calculations were carried out for the key [4+2] cycloaddition step considering enzyme-catalyzed biosynthesis of Spinosyn A in a model reaction, where a reliable example of a biological Diels-Alder reaction was reported experimentally. In the present study it was demonstrated that the [4+2] cycloaddition reaction may benefit from moving along the energetically balanced reaction coordinate, which enabled the catalytic rate enhancement of the [4+2] cycloaddition pathway involving a single transition state. Modeling of such a system with coordination of three amino acids indicated a reliable decrease of activation energy by ~18.0 kcal/mol as compared to a non-catalytic transformation.

Show MeSH
Related in: MedlinePlus