Combined QM(DFT)/MM molecular dynamics simulations of the deamination of cytosine by yeast cytosine deaminase (yCD). Issue 13 (26th January 2016)

• Record Type: Journal Article
• Authors: Zhang, Xin; Zhao, Yuan; Yan, Honggao; Cao, Zexing; Mo, Yirong
• Is Part Of: Journal of computational chemistry. Volume 37:Issue 13(2016)
• Page Start: 1163
• Page End: 1174
• Publication Date: 2016-01-26
• Subjects: molecular dynamics -- combined QM/MM -- DFT -- cytosine -- enzymatic catalysis; Chemistry -- Data processing -- Periodicals; 542.85
• DOI: 10.1002/jcc.24306
• Languages: English
• ISSNs: 0192-8651

Abstract

Abstract : Extensive combined quantum mechanical (B3LYP/6‐31G*) and molecular mechanical (QM/MM) molecular dynamics simulations have been performed to elucidate the hydrolytic deamination mechanism of cytosine to uracil catalyzed by the yeast cytosine deaminase (yCD). Though cytosine has no direct binding to the zinc center, it reacts with the water molecule coordinated to zinc, and the adjacent conserved Glu64 serves as a general acid/base to shuttle protons from water to cytosine. The overall reaction consists of several proton‐transfer processes and nucleophilic attacks. A tetrahedral intermediate adduct of cytosine and water binding to zinc is identified and similar to the crystal structure of yCD with the inhibitor 2‐pyrimidinone. The rate‐determining step with the barrier of 18.0 kcal/mol in the whole catalytic cycle occurs in the process of uracil departure where the proton transfer from water to Glu64 and nucleophilic attack of the resulting hydroxide anion to C2 of the uracil ring occurs synchronously. © 2016 Wiley Periodicals, Inc. Abstract : Yeast cytosine deaminase (yCD) is an enzyme responsible for the activation process of anticancer drugs, and efforts have been put to understand its structure and functions. Computational simulations were performed in order to elucidate how yCD catalyzes the hydrolytic deamination of cytosine to uracil. While the computations show that Glu64 serves as the proton shuttle in various reaction steps, the decisive step was identified as the release of uracil from its trapped state.