Mechanistic Implications of Reductive Co–C Bond Cleavage in B 12 -Dependent Methylmalonyl CoA Mutase
[1];
[2];
[3]
- Computational Biology and Bioinformatics Group, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
- Molecular Modeling &, Design at leadXpro Villigen, Canton of Aargau, Switzerland
- Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States
Vitamin B12-dependent enzymes catalyze several difficult radical reactions. However, there are fundamental open questions that need to be addressed to fully understand the formation of highly reactive radical species, its dynamics and interaction with substrate and enzyme. In this work, the possible role of a Proton Coupled Electron Transfer (PCET) pathway concurrent with the Co-C bond activation was investigated. Car-Parrinello molecular dynamics (CPMD) was performed within a QM/MM framework on a reduced AdoCbl cofactor, which was taken as a post-PCET initial step in the activation of the AdoCbl-dependent methylmalonyl CoA mutase (MCM) enzyme. The calculated free energy profile reveals two possible pathways with similar energies, stepwise (I) and concerted (II) for the reductive Co-C cleavage and subsequent H-abstraction. The concerted pathway may be preferred kinetically, because it avoids the formation of a high-energy radical intermediate with possibly a larger recrossing rate. Our results are consistent with the previous proposal of the conductor hypothesis, indicating the explicit role of cob(II)alamin in stabilizing the radical intermediate involved in H-atom transfer.
- Research Organization:
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC05-76RL01830
- OSTI ID:
- 1503559
- Report Number(s):
- PNNL-SA-138248
- Journal Information:
- Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry, Vol. 123, Issue 10; ISSN 1520-6106
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
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