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

Toshiaki Matsubara, Michel Dupuis, Misako Aida

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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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ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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