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 language | English |
|---|---|
| Pages (from-to) | 9965-9974 |
| Number of pages | 10 |
| Journal | Journal of Physical Chemistry B |
| Volume | 111 |
| Issue number | 33 |
| DOIs | |
| Publication status | Published - Aug 23 2007 |
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ASJC Scopus subject areas
- Physical and Theoretical Chemistry
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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 journal › Article
}
TY - JOUR
T1 - Ab initio ONIOM-Molecular Dynamics (MD) study on the deamination reaction by cytidine deaminase
AU - Matsubara, Toshiaki
AU - Dupuis, Michel
AU - Aida, Misako
PY - 2007/8/23
Y1 - 2007/8/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34548559131&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548559131&partnerID=8YFLogxK
U2 - 10.1021/jp072732k
DO - 10.1021/jp072732k
M3 - Article
C2 - 17661509
AN - SCOPUS:34548559131
VL - 111
SP - 9965
EP - 9974
JO - Journal of Physical Chemistry B Materials
JF - Journal of Physical Chemistry B Materials
SN - 1520-6106
IS - 33
ER -