Molecular dynamics study on class A β-lactamase

Hydrogen bond network among the functional groups of penicillin G and side chains of the conserved residues in the active site

Yasuyuki Fujii, Noriaki Okimoto, Masayuki Hata, Tetsu Narumi, Kenji Yasuoka, Ryutaro Susukita, Atsushi Suenaga, Noriyuki Futatsugi, Takahiro Koishi, Hideaki Furusawa, Atsushi Kawai, Toshikazu Ebisuzaki, Saburo Neya, Tyuji Hoshino

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Molecular dynamics simulation was performed on class A β-lactamase binding penicillin G (pen G). The structure of the acyl enzyme intermediate (AEI) was derived from the crystallographic data of the clavulanic acid bound enzyme. To execute the simulation precisely, the AEI was solvated by nearly 8000 water molecules and the no-cutoff (NCO) method was applied to the calculation of the Coulomb term. The Coulomb term calculation was accelerated with MDGRAPE-2 hardware. In the first step of this study, the relability of the NCO method was confirmed by comparing experimental and computational B-factors. We confirmed that the NCO method is much more reliable than the particle mesh Ewald and generalized Born methods. Hence the NCO method was applied for the simulation on AEI. The integrated simulation time was 1.2 ns. It was found from the simulation that Ser130, Asn132, Ser235, Gly237, and Arg244 cooperatively restricted the mobility of pen G moiety by making salt bridges among the side chains of these residues and the C3-carboxyl or C6-amide group of the substrate. The oxyanion hole composed of N atom in the main chain of Ser70 and Gly237 was properly reproduced under aqueous condition. The simulation also shows that it is impossible for Glu166 to act as a general base in the acylation of pen G because the average distance between Glu166 carboxyl oxygens and Ser700γ is too far for direct proton transfer (5.2 and 5.5 Å, respectively) and there is no water molecule between Glu166 carboxylate and Ser700γ. Molecular dynamics simulation on the substrate free enzyme (SFE) was also carried out and compared with AEI. While no drastic change due to the substrate binding was observed in both the secondary structure and the positions of catalytic residues of the enzyme, the mobility of the catalytic water molecule was strongly restricted by the presence of the substrate.

Original languageEnglish
Pages (from-to)10274-10283
Number of pages10
JournalJournal of Physical Chemistry B
Volume107
Issue number37
Publication statusPublished - 2003 Sep 18

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penicillin
Penicillin G
Functional groups
Molecular dynamics
enzymes
Hydrogen bonds
Enzymes
hydrogen bonds
molecular dynamics
cut-off
simulation
Substrates
Molecules
Water
water
molecules
acylation
Acylation
Clavulanic Acid
Proton transfer

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry

Cite this

Molecular dynamics study on class A β-lactamase : Hydrogen bond network among the functional groups of penicillin G and side chains of the conserved residues in the active site. / Fujii, Yasuyuki; Okimoto, Noriaki; Hata, Masayuki; Narumi, Tetsu; Yasuoka, Kenji; Susukita, Ryutaro; Suenaga, Atsushi; Futatsugi, Noriyuki; Koishi, Takahiro; Furusawa, Hideaki; Kawai, Atsushi; Ebisuzaki, Toshikazu; Neya, Saburo; Hoshino, Tyuji.

In: Journal of Physical Chemistry B, Vol. 107, No. 37, 18.09.2003, p. 10274-10283.

Research output: Contribution to journalArticle

Fujii, Y, Okimoto, N, Hata, M, Narumi, T, Yasuoka, K, Susukita, R, Suenaga, A, Futatsugi, N, Koishi, T, Furusawa, H, Kawai, A, Ebisuzaki, T, Neya, S & Hoshino, T 2003, 'Molecular dynamics study on class A β-lactamase: Hydrogen bond network among the functional groups of penicillin G and side chains of the conserved residues in the active site', Journal of Physical Chemistry B, vol. 107, no. 37, pp. 10274-10283.
Fujii, Yasuyuki ; Okimoto, Noriaki ; Hata, Masayuki ; Narumi, Tetsu ; Yasuoka, Kenji ; Susukita, Ryutaro ; Suenaga, Atsushi ; Futatsugi, Noriyuki ; Koishi, Takahiro ; Furusawa, Hideaki ; Kawai, Atsushi ; Ebisuzaki, Toshikazu ; Neya, Saburo ; Hoshino, Tyuji. / Molecular dynamics study on class A β-lactamase : Hydrogen bond network among the functional groups of penicillin G and side chains of the conserved residues in the active site. In: Journal of Physical Chemistry B. 2003 ; Vol. 107, No. 37. pp. 10274-10283.
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AU - Hata, Masayuki

AU - Narumi, Tetsu

AU - Yasuoka, Kenji

AU - Susukita, Ryutaro

AU - Suenaga, Atsushi

AU - Futatsugi, Noriyuki

AU - Koishi, Takahiro

AU - Furusawa, Hideaki

AU - Kawai, Atsushi

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AU - Neya, Saburo

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