A QM/MM study on the last two steps of the catalytic cycle of acetohydroxyacid synthase

Gonzalo Jaña, Verónica Jiménez, Jordi Villà-Freixa, Xavier Prat-Resina, Eduardo Delgado, Joel B. Alderete

Resultado de la investigación: Article

7 Citas (Scopus)

Resumen

The acetohydroxyacid synthase (AHAS) is a thiamin diphosphate dependent enzyme that participates in the biosynthetic pathway of branched-chain amino acids. The catalytic cycle of AHAS consists of five steps and the first three steps are analogues to other thiamin diphosphate dependent enzymes, but some mechanism aspect of the last two steps of the AHAS catalytic cycle remain unclear. We have modeled the last two catalytic steps of the AHAS, using a combined quantum mechanical and molecular mechanical method (QM/MM). Substrates (pyruvate and hydroxyethylthiamine diphosphate anion) and three important amino acids (Arg380, Gly116 and Glu139) of the active site were considered into the QM region. A complete characterization of the potential energy surface was performed using the AM1/CHARMM27 approach. In order to improve the semi-empirical calculations, the AM1/MM potential energy surface was corrected at B3LYP/6-31G(d,p) level (B3LYP/6-31G(d,p)//AM1/MM). Our results show that the protein environment is crucial to provide an adequate description of the reaction mechanisms. This fact is consequence of the increase of the substrate polarization by the enzyme environment. In this sense, the largest substrate polarization is observed when selected amino acid residues are included within the QM region in B3LYP/6-31G(d,p)//AM1/MM calculations.

Idioma originalEnglish
Páginas (desde-hasta)159-166
Número de páginas8
PublicaciónComputational and Theoretical Chemistry
Volumen966
N.º1-3
DOI
EstadoPublished - 1 ene 2011

Huella dactilar

diphosphates
Thiamine Pyrophosphate
Potential energy surfaces
thiamine
amino acids
enzymes
cycles
Substrates
Enzymes
Polarization
Amino Acids
Branched Chain Amino Acids
Diphosphates
potential energy
Biosynthetic Pathways
pyruvates
Pyruvic Acid
Anions
Catalytic Domain
polarization

ASJC Scopus subject areas

  • Biochemistry
  • Condensed Matter Physics
  • Physical and Theoretical Chemistry

Citar esto

Jaña, Gonzalo ; Jiménez, Verónica ; Villà-Freixa, Jordi ; Prat-Resina, Xavier ; Delgado, Eduardo ; Alderete, Joel B. / A QM/MM study on the last two steps of the catalytic cycle of acetohydroxyacid synthase. En: Computational and Theoretical Chemistry. 2011 ; Vol. 966, N.º 1-3. pp. 159-166.
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abstract = "The acetohydroxyacid synthase (AHAS) is a thiamin diphosphate dependent enzyme that participates in the biosynthetic pathway of branched-chain amino acids. The catalytic cycle of AHAS consists of five steps and the first three steps are analogues to other thiamin diphosphate dependent enzymes, but some mechanism aspect of the last two steps of the AHAS catalytic cycle remain unclear. We have modeled the last two catalytic steps of the AHAS, using a combined quantum mechanical and molecular mechanical method (QM/MM). Substrates (pyruvate and hydroxyethylthiamine diphosphate anion) and three important amino acids (Arg380, Gly116 and Glu139) of the active site were considered into the QM region. A complete characterization of the potential energy surface was performed using the AM1/CHARMM27 approach. In order to improve the semi-empirical calculations, the AM1/MM potential energy surface was corrected at B3LYP/6-31G(d,p) level (B3LYP/6-31G(d,p)//AM1/MM). Our results show that the protein environment is crucial to provide an adequate description of the reaction mechanisms. This fact is consequence of the increase of the substrate polarization by the enzyme environment. In this sense, the largest substrate polarization is observed when selected amino acid residues are included within the QM region in B3LYP/6-31G(d,p)//AM1/MM calculations.",
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A QM/MM study on the last two steps of the catalytic cycle of acetohydroxyacid synthase. / Jaña, Gonzalo; Jiménez, Verónica; Villà-Freixa, Jordi; Prat-Resina, Xavier; Delgado, Eduardo; Alderete, Joel B.

En: Computational and Theoretical Chemistry, Vol. 966, N.º 1-3, 01.01.2011, p. 159-166.

Resultado de la investigación: Article

TY - JOUR

T1 - A QM/MM study on the last two steps of the catalytic cycle of acetohydroxyacid synthase

AU - Jaña, Gonzalo

AU - Jiménez, Verónica

AU - Villà-Freixa, Jordi

AU - Prat-Resina, Xavier

AU - Delgado, Eduardo

AU - Alderete, Joel B.

PY - 2011/1/1

Y1 - 2011/1/1

N2 - The acetohydroxyacid synthase (AHAS) is a thiamin diphosphate dependent enzyme that participates in the biosynthetic pathway of branched-chain amino acids. The catalytic cycle of AHAS consists of five steps and the first three steps are analogues to other thiamin diphosphate dependent enzymes, but some mechanism aspect of the last two steps of the AHAS catalytic cycle remain unclear. We have modeled the last two catalytic steps of the AHAS, using a combined quantum mechanical and molecular mechanical method (QM/MM). Substrates (pyruvate and hydroxyethylthiamine diphosphate anion) and three important amino acids (Arg380, Gly116 and Glu139) of the active site were considered into the QM region. A complete characterization of the potential energy surface was performed using the AM1/CHARMM27 approach. In order to improve the semi-empirical calculations, the AM1/MM potential energy surface was corrected at B3LYP/6-31G(d,p) level (B3LYP/6-31G(d,p)//AM1/MM). Our results show that the protein environment is crucial to provide an adequate description of the reaction mechanisms. This fact is consequence of the increase of the substrate polarization by the enzyme environment. In this sense, the largest substrate polarization is observed when selected amino acid residues are included within the QM region in B3LYP/6-31G(d,p)//AM1/MM calculations.

AB - The acetohydroxyacid synthase (AHAS) is a thiamin diphosphate dependent enzyme that participates in the biosynthetic pathway of branched-chain amino acids. The catalytic cycle of AHAS consists of five steps and the first three steps are analogues to other thiamin diphosphate dependent enzymes, but some mechanism aspect of the last two steps of the AHAS catalytic cycle remain unclear. We have modeled the last two catalytic steps of the AHAS, using a combined quantum mechanical and molecular mechanical method (QM/MM). Substrates (pyruvate and hydroxyethylthiamine diphosphate anion) and three important amino acids (Arg380, Gly116 and Glu139) of the active site were considered into the QM region. A complete characterization of the potential energy surface was performed using the AM1/CHARMM27 approach. In order to improve the semi-empirical calculations, the AM1/MM potential energy surface was corrected at B3LYP/6-31G(d,p) level (B3LYP/6-31G(d,p)//AM1/MM). Our results show that the protein environment is crucial to provide an adequate description of the reaction mechanisms. This fact is consequence of the increase of the substrate polarization by the enzyme environment. In this sense, the largest substrate polarization is observed when selected amino acid residues are included within the QM region in B3LYP/6-31G(d,p)//AM1/MM calculations.

KW - Acetolactate synthase

KW - Ahas

KW - Potential energy surface

KW - Reaction mechanism

KW - Thiamine diphosphate

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U2 - 10.1016/j.comptc.2011.02.030

DO - 10.1016/j.comptc.2011.02.030

M3 - Article

AN - SCOPUS:80655144018

VL - 966

SP - 159

EP - 166

JO - Computational and Theoretical Chemistry

JF - Computational and Theoretical Chemistry

SN - 2210-271X

IS - 1-3

ER -