Hybrid quantum and molecular mechanical (QM/MM) studies on the pyruvate to L-lactate interconversion in L-lactate dehydrogenase

Shoba Ranganathan, Jill E. Gready

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Hybrid quantum mechanical (QM) and molecular mechanical (MM) calculations were undertaken to study the catalytic mechanism for the interconversion of pyruvate to L-lactate by the enzyme L-lactate dehydrogenase, in the presence of the cofactor nicotinamide adenine dinucleotide (NAD). The QM system comprised molecular species or fragments involved in the chemical bond-making and -breaking events: the substrate pyruvate, trans-1-methyldihydronicotinamide (a fragment of the cofactor), and His-195. The remainder of the enzyme, cofactor, and water molecules made up the MM system. The QM/MM potential energy surface was calculated as a grid of points for two reaction coordinates representing the transfers of a proton and of a hydride ion. From this surface, two transition states for the two transfers were identified, with the hydride-ion transfer step indicated as being rate-limiting and preceding the proton transfer. The intermediate is deprotonated L-lactate. This result disagrees with our earlier all-QM results for a "supermolecule" system consisting of substrate, cofactor and key active-site residue fragments ( Ranganathan, S.; Gready, J. E. Faraday Trans. 1994, 90 2047), which indicated protonation preceded hydride-ion transfer. Structures, energies, and atomic charges for reactant and product complexes and for the two transition states are reported.

LanguageEnglish
Pages5614-5618
Number of pages5
JournalJournal of Physical Chemistry B
Volume101
Issue number28
Publication statusPublished - 10 Jul 1997
Externally publishedYes

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pyruvates
lactates
dehydrogenases
Pyruvic Acid
L-Lactate Dehydrogenase
Hydrides
Lactic Acid
Ions
hydrides
Enzymes
fragments
Potential energy surfaces
Proton transfer
Chemical bonds
Protonation
Coenzymes
Substrates
enzymes
NAD
Protons

Cite this

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title = "Hybrid quantum and molecular mechanical (QM/MM) studies on the pyruvate to L-lactate interconversion in L-lactate dehydrogenase",
abstract = "Hybrid quantum mechanical (QM) and molecular mechanical (MM) calculations were undertaken to study the catalytic mechanism for the interconversion of pyruvate to L-lactate by the enzyme L-lactate dehydrogenase, in the presence of the cofactor nicotinamide adenine dinucleotide (NAD). The QM system comprised molecular species or fragments involved in the chemical bond-making and -breaking events: the substrate pyruvate, trans-1-methyldihydronicotinamide (a fragment of the cofactor), and His-195. The remainder of the enzyme, cofactor, and water molecules made up the MM system. The QM/MM potential energy surface was calculated as a grid of points for two reaction coordinates representing the transfers of a proton and of a hydride ion. From this surface, two transition states for the two transfers were identified, with the hydride-ion transfer step indicated as being rate-limiting and preceding the proton transfer. The intermediate is deprotonated L-lactate. This result disagrees with our earlier all-QM results for a {"}supermolecule{"} system consisting of substrate, cofactor and key active-site residue fragments ( Ranganathan, S.; Gready, J. E. Faraday Trans. 1994, 90 2047), which indicated protonation preceded hydride-ion transfer. Structures, energies, and atomic charges for reactant and product complexes and for the two transition states are reported.",
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Hybrid quantum and molecular mechanical (QM/MM) studies on the pyruvate to L-lactate interconversion in L-lactate dehydrogenase. / Ranganathan, Shoba; Gready, Jill E.

In: Journal of Physical Chemistry B, Vol. 101, No. 28, 10.07.1997, p. 5614-5618.

Research output: Contribution to journalArticleResearchpeer-review

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