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Developing Active Site Models of ODCase—from Large Quantum Models to a QM/MM Approach

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Orotidine Monophosphate Decarboxylase

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 238))

Abstract

The catalytic mechanism of orotidine monophosphate decarboxylase (ODCase) has been modeled using density functional theory with the B3LYP functional. Barriers for three different mechanisms have been calculated using large QM and QM/MM models. A concerted protonation mechanism where TS stabilization is provided only by the positive Lys93 has a high barrier around 35 kcal/mol. QM/MM calculations confirm the results obtained using QM models. For a base protonation mechanism, O2 protonation gives a barrier for decarboxylation of 26 kcal/mol. Extensions to this QM model indicate that the cost of protonation may be underestimated and the support for the base protonation mechanism is uncertain. An initial QM/MM investigation of a stepwise mechanism, where water molecules seem to play an important role for TS stabilization, gives the most promising results with an estimated barrier of 22 kcal/mol.

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Abbreviations

DFT :

Density functional theory

MM :

Molecular mechanics

OMP :

Orotidine 5′-monophosphate

ODCase :

Orotidine 5′-monophosphate decarboxylase

QM :

Quantum mechanics

QM/MM :

Quantum mechanics/molecular mechanics

TS :

Transition state

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Acknowledgments

We would like to thank Arieh Warshel and Marek Ŝtrajbl for kindly providing their structures of the ODCase reactants and intermediates. We would also like to thank the National Supercomputer Center (Sweden) for a generous grant of computer time at the SGI3800.

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Authors and Affiliations

  1. Department of Physics, Stockholm Center for Physics, Astronomy and Biotechnology, Stockholm University, 106 91 , Stockholm, Sweden

    Marcus Lundberg, Margareta R. A. Blomberg & Per E. M. Siegbahn

Authors
  1. Marcus Lundberg
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  2. Margareta R. A. Blomberg
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  3. Per E. M. Siegbahn
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Corresponding author

Correspondence to Marcus Lundberg .

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J.K. Lee

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Lundberg, M., Blomberg, M.R.A., Siegbahn, P.E.M. Developing Active Site Models of ODCase—from Large Quantum Models to a QM/MM Approach. In: Lee, J. (eds) Orotidine Monophosphate Decarboxylase. Topics in Current Chemistry, vol 238. Springer, Berlin, Heidelberg. https://doi.org/10.1007/b94540

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  • DOI: https://doi.org/10.1007/b94540

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-20566-1

  • Online ISBN: 978-3-540-40039-4

  • eBook Packages: Springer Book Archive

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