Ab initio ONIOM-Molecular Dynamics (MD) study on the deamination reaction by cytidine deaminase

Toshiaki Matsubara, Michel Dupuis, Misako Aida

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

We applied the ONIOM-molecular dynamics (MD) method to the hydrolytic deamination of cytidine by cytidine deaminase, which is an essential step of the activation process of the anticancer drug inside the human body. The direct MD simulations were performed for the realistic model of cytidine deaminase by calculating the energy and its gradient by the ab initio ONIOM method on the fly. The ONIOM-MD calculations including the thermal motion show that the neighboring amino acid residue is an important factor of the environmental effects and significantly affects not only the geometry and energy of the substrate trapped in the pocket of the active site but also the elementary step of the catalytic reaction. We successfully simulate the second half of the catalytic cycle, which has been considered to involve the rate-determining step, and reveal that the rate-determining step is the release of the NH3 molecule.

Original languageEnglish
Pages (from-to)9965-9974
Number of pages10
JournalJournal of Physical Chemistry B
Volume111
Issue number33
DOIs
Publication statusPublished - Aug 23 2007

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Cytidine Deaminase
Molecular dynamics
molecular dynamics
Cytidine
Environmental impact
Amino acids
human body
Chemical activation
amino acids
Amino Acids
drugs
Molecules
Geometry
Computer simulation
activation
Substrates
Pharmaceutical Preparations
gradients
cycles
energy

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry

Cite this

Ab initio ONIOM-Molecular Dynamics (MD) study on the deamination reaction by cytidine deaminase. / Matsubara, Toshiaki; Dupuis, Michel; Aida, Misako.

In: Journal of Physical Chemistry B, Vol. 111, No. 33, 23.08.2007, p. 9965-9974.

Research output: Contribution to journalArticle

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