Ab initio ONIOM-molecular dynamics (MD) study on the deamination reaction by cytidine deaminase

Area of Science:

• Biochemistry
• Computational Chemistry
• Enzymology

Background:

• Cytidine deaminase is crucial for activating anticancer drugs.
• Understanding its mechanism is key to drug development.

Purpose of the Study:

• To investigate the hydrolytic deamination of cytidine by cytidine deaminase.
• To elucidate the rate-determining step in the catalytic cycle.

Main Methods:

• ONIOM-molecular dynamics (MD) method applied to a realistic model of cytidine deaminase.
• Ab initio ONIOM calculations for energy and gradient determination.
• Simulations included thermal motion and environmental effects.

Main Results:

• Neighboring amino acid residues significantly impact substrate geometry, energy, and catalytic reaction.
• The second half of the catalytic cycle, including the rate-determining step, was successfully simulated.
• The release of the ammonia (NH3) molecule was identified as the rate-determining step.

Conclusions:

• Environmental effects from amino acid residues are critical for cytidine deaminase function.
• The ONIOM-MD method provides valuable insights into enzyme-catalyzed reactions.
• Accurate simulation of the rate-determining step aids in understanding drug activation.