Ab initio and density functional theory studies of the catalytic mechanism for ester hydrolysis in serine hydrolases

Ching-Han Hu, Tore Brinck, Karl Hult

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

We present results from ab initio and density functional theory studies of the mechanism for serine hydrolase catalyzed ester hydrolysis. A model system containing both the catalytic triad and the oxyanion hole was studied. The catalytic triad was represented by formate anion, imidazole, and methanol. The oxyanion hole was represented by two water molecules. Methyl formate was used as the substrate. In the acylation step, our computations show that the cooperation of the Asp group and oxyanion hydrogen bonds is capable of lowering the activation barrier by about 15 kcal/mol. The transition state leading to the first tetrahedral intermediate in the acylation step is rate limiting with an activation barrier (ΔE0) of 13.4 kcal/mol. The activation barrier in the deacylation step is smaller. The double-proton-transfer mechanism is energetically unfavorable by about 2 kcal/mol. The bonds between the Asp group and the His group, and the hydrogen bonds in the oxyanion hole, increase in strength going from the Michaelis complex toward the transition state and the tetrahedral intermediate. In the acylation step, the tetrahedral intermediate is a very shallow minimum on the energy surface and is not viable when molecular vibrations are included.

Original languageEnglish
Pages (from-to)89-103
Number of pages15
JournalInternational Journal of Quantum Chemistry
Volume69
Issue number1
DOIs
Publication statusPublished - 1998 Jan 1

Fingerprint

Acylation
Hydrolases
acylation
Serine
Density functional theory
hydrolysis
esters
Hydrolysis
Esters
formic acid
Chemical activation
density functional theory
Hydrogen bonds
formates
activation
Molecular vibrations
Proton transfer
hydrogen bonds
Interfacial energy
Anions

All Science Journal Classification (ASJC) codes

  • Atomic and Molecular Physics, and Optics
  • Condensed Matter Physics
  • Physical and Theoretical Chemistry

Cite this

@article{d9442dc3fe004294899519615cd53218,
title = "Ab initio and density functional theory studies of the catalytic mechanism for ester hydrolysis in serine hydrolases",
abstract = "We present results from ab initio and density functional theory studies of the mechanism for serine hydrolase catalyzed ester hydrolysis. A model system containing both the catalytic triad and the oxyanion hole was studied. The catalytic triad was represented by formate anion, imidazole, and methanol. The oxyanion hole was represented by two water molecules. Methyl formate was used as the substrate. In the acylation step, our computations show that the cooperation of the Asp group and oxyanion hydrogen bonds is capable of lowering the activation barrier by about 15 kcal/mol. The transition state leading to the first tetrahedral intermediate in the acylation step is rate limiting with an activation barrier (ΔE0) of 13.4 kcal/mol. The activation barrier in the deacylation step is smaller. The double-proton-transfer mechanism is energetically unfavorable by about 2 kcal/mol. The bonds between the Asp group and the His group, and the hydrogen bonds in the oxyanion hole, increase in strength going from the Michaelis complex toward the transition state and the tetrahedral intermediate. In the acylation step, the tetrahedral intermediate is a very shallow minimum on the energy surface and is not viable when molecular vibrations are included.",
author = "Ching-Han Hu and Tore Brinck and Karl Hult",
year = "1998",
month = "1",
day = "1",
doi = "10.1002/(SICI)1097-461X(1998)69:1<89::AID-QUA11>3.0.CO;2-0",
language = "English",
volume = "69",
pages = "89--103",
journal = "International Journal of Quantum Chemistry",
issn = "0020-7608",
publisher = "John Wiley and Sons Inc.",
number = "1",

}

Ab initio and density functional theory studies of the catalytic mechanism for ester hydrolysis in serine hydrolases. / Hu, Ching-Han; Brinck, Tore; Hult, Karl.

In: International Journal of Quantum Chemistry, Vol. 69, No. 1, 01.01.1998, p. 89-103.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ab initio and density functional theory studies of the catalytic mechanism for ester hydrolysis in serine hydrolases

AU - Hu, Ching-Han

AU - Brinck, Tore

AU - Hult, Karl

PY - 1998/1/1

Y1 - 1998/1/1

N2 - We present results from ab initio and density functional theory studies of the mechanism for serine hydrolase catalyzed ester hydrolysis. A model system containing both the catalytic triad and the oxyanion hole was studied. The catalytic triad was represented by formate anion, imidazole, and methanol. The oxyanion hole was represented by two water molecules. Methyl formate was used as the substrate. In the acylation step, our computations show that the cooperation of the Asp group and oxyanion hydrogen bonds is capable of lowering the activation barrier by about 15 kcal/mol. The transition state leading to the first tetrahedral intermediate in the acylation step is rate limiting with an activation barrier (ΔE0) of 13.4 kcal/mol. The activation barrier in the deacylation step is smaller. The double-proton-transfer mechanism is energetically unfavorable by about 2 kcal/mol. The bonds between the Asp group and the His group, and the hydrogen bonds in the oxyanion hole, increase in strength going from the Michaelis complex toward the transition state and the tetrahedral intermediate. In the acylation step, the tetrahedral intermediate is a very shallow minimum on the energy surface and is not viable when molecular vibrations are included.

AB - We present results from ab initio and density functional theory studies of the mechanism for serine hydrolase catalyzed ester hydrolysis. A model system containing both the catalytic triad and the oxyanion hole was studied. The catalytic triad was represented by formate anion, imidazole, and methanol. The oxyanion hole was represented by two water molecules. Methyl formate was used as the substrate. In the acylation step, our computations show that the cooperation of the Asp group and oxyanion hydrogen bonds is capable of lowering the activation barrier by about 15 kcal/mol. The transition state leading to the first tetrahedral intermediate in the acylation step is rate limiting with an activation barrier (ΔE0) of 13.4 kcal/mol. The activation barrier in the deacylation step is smaller. The double-proton-transfer mechanism is energetically unfavorable by about 2 kcal/mol. The bonds between the Asp group and the His group, and the hydrogen bonds in the oxyanion hole, increase in strength going from the Michaelis complex toward the transition state and the tetrahedral intermediate. In the acylation step, the tetrahedral intermediate is a very shallow minimum on the energy surface and is not viable when molecular vibrations are included.

UR - http://www.scopus.com/inward/record.url?scp=0002797667&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0002797667&partnerID=8YFLogxK

U2 - 10.1002/(SICI)1097-461X(1998)69:1<89::AID-QUA11>3.0.CO;2-0

DO - 10.1002/(SICI)1097-461X(1998)69:1<89::AID-QUA11>3.0.CO;2-0

M3 - Article

VL - 69

SP - 89

EP - 103

JO - International Journal of Quantum Chemistry

JF - International Journal of Quantum Chemistry

SN - 0020-7608

IS - 1

ER -