Computational Insights into the Mechanism of Radical Generation in B<sub>12</sub>-Dependent Methylmalonyl-CoA Mutase

Kwiecień, Renata A.; Khavrutskii, Ilja V.; Musaev, Djamaladdin G.; Morokuma, Keiji; Banerjee, Ruma; Paneth, Piotr

doi:10.1021/ja056333j

Cited by 77 publications

(111 citation statements)

References 46 publications

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“…The same optimization algorithm has previously been used to identify two transition states in mammalian glutathione peroxidase (GPx) 13 and a transition state for homolysis of the Co-C bond in methylmalonyl-CoA mutase. 14 The ability to locate transition states makes it possible to see how the protein matrix affects the reaction coordinate and to quantify the effects on reaction rates. Optimization approaches are appropriate when there are no major changes in protein structure, but cannot describe major changes in protein conformation.…”

Section: Introductionmentioning

confidence: 99%

Transition States in a Protein Environment − ONIOM QM:MM Modeling of Isopenicillin N Synthesis

Lundberg

Kawatsu

Vreven

et al. 2008

J. Chem. Theory Comput.

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117

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Abstract.To highlight the role of the protein in metal enzyme catalysis, we optimize ONIOM QM:MM transition states and intermediates for the full reaction of the non-heme iron enzyme isopenicillin N synthase (IPNS). Optimizations of transition states in large protein systems are possible using our new geometry optimizer with quadratic coupling between the QM and MM regions. [Vreven, T. et. al., Mol. Phys. 2006, 104, 701-704]. To highlight the effect of the metal center, results from the protein model are compared to results from an active site model containing only the metal center and coordinating residues [Lundberg, M. et. al., Biochemistry 2008, 47, 1031-1042. The analysis suggests that the main catalytic effect comes from the metal center, while the protein controls the reactivity to achieve high product specificity. As an example, hydrophobic residues align the valine substrate radical in a favorable conformation for thiazolidine ring closure and contribute to product selectivity and high stereospecificity.

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Section: Introductionmentioning

confidence: 99%

Transition States in a Protein Environment − ONIOM QM:MM Modeling of Isopenicillin N Synthesis

Lundberg

Kawatsu

Vreven

et al. 2008

J. Chem. Theory Comput.

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117

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“…Another recent theoretical study (23) used the ONIOM QM/MM approach and obtained a barrier of Ϸ18 kcal/mol for stretching the Co-C bond in the enzyme up to 3.2 Å. It was then argued that the Co-C is not a good reaction coordinate.…”

mentioning

confidence: 99%

“…It is possible, of course, to hold the protein fixed and to obtain an upper limit for the proposed effect, but this was not reported in ref. 23.…”

mentioning

confidence: 99%

A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes

Sharma

Chu²,

Olsson³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

120

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The catalytic power of enzymes containing coenzyme B12 cofactor has been, in some respects, the ''last bastion'' for the strain hypothesis. The present work explores the origin of this effect by using simulation methods that overcome the sampling difficulties of previous energy minimization studies. It is found that the major part of the catalytic effect is due to the electrostatic interaction between the ribose and the protein, and that the strain contribution is very small. Remarkably, enzymes can use electrostatic effects even in a radical process, when the charge distribution of the reacting fragments does not change significantly during the reaction. Electrostatic catalysis can, in such cases, be obtained by attaching a polar group to the leaving fragment and designing an active site that interacts more strongly with this group in the product state than in the reactant state. The finding that evolution had to use this trick provides further evidence to the observation that it is extremely hard to catalyze enzymatic reactions by nonelectrostatic factors. The trick used by B12 enzymes may, in fact, be a very powerful new strategy in enzyme design.simulation of enzymatic reactions ͉ strain effect ͉ transition state stabilization

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“…Consequently, various properties have been studied, including electron densities and reduction potentials determination [69,76,88,91,96], the comparison of DFT and CASSCF electronic structure data of truncated models of methylcobalamin species [70,71,74,81,85], the infl uence of various factors on the Co-C bond forming and cleavage in methyl-and 5-adenosylcobalamin models [68,[72][73][74][75][76]79,80,83,84,89,90,92,94,97,99,100], and excited states, spectroscopy and photo-dissociation analysis of vitamin B 12 species [78,82,86,87,93,95,98]. We used DFT calculations on Me-Cbl models to calculate total energy as a function of Co-C bond distance as the bond is stretched [39].…”

Section: Density Functional Theory (Dft) and Quantum Mechanics/ Molecmentioning

confidence: 99%

The Nature of the Co-C Bond Cleavage Processes in Methylcob(II)Alamin and Adenosylcob(III)Alamin

Spataru¹,

Fernández²

2016

ChemJMold

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Abstract. Unfortunately, there are still signifi cant disagreements between experimental and theoretical data of rate constants, energy barriers for Co-C bond cleavage process and coordination numbers of vitamin B 12 coenzyme species in spite of the remarkable efforts done by research community. Therefore, no grounded mechanisms for Co-C vitamin B 12 coenzyme bond breaking process and subsequent reactions have been found up to now. The infl uence of the mixing orbitals e.g. Pseudo-Jahn-Teller and similar effects on the reactions paths of bond-cleavage mechanisms of vitamin B 12 co-factors must be taken into account by utilizing multi-reference methods, in particular multiconfi gurational self-consistent fi eld (MCSCF) method. Then, the change in total energy along the normal coordinate Q for the stretching mode including Co-C and Co-N bonds in vitamin B 12 cofactors is expected due to a "vibronic" coupling term, which couples an excited state and ground state by a second order derivative potential-energy operator. The strong state mixing effect is expected to lead to low energy barriers and to Co-C and Co-N axial bond cleavage events in agreement with experimental data. Afterward, the updated mechanisms of vitamin B 12 bio-processes can be determined.Keywords: vitamin B 12 , mechanism, bio-catalysis, Pseudo-Jahn-Teller effect, DFT, MCSCF. Received: December 2015/ Revised fi nal: February 2016/ Accepted: February 2016 IntroductionVitamin B 12 cofactor is one of eight B vitamins and is involved in mammalian cellular metabolism, infl uencing amino acid and DNA synthesis [1] and hematopoiesis. The best known human physiological function of vitamin B 12 is its role in promoting normal health in the brain and nervous system. Vitamin B 12 anemia can cause such neurologic dysfunction as weakness, fatigue, light-headedness, rapid heartbeat, rapid breathing, pale skin color, bruising, and bleeding (including bleeding gums). The more severe vitamin B 12 anemia dysfunctions are characterized by tingling or numbness of the fi ngers and toes, diffi culty walking, mood changes, depression, memory loss, disorientation and, in most severe cases, dementia [2]. Vitamin B 12 defi ciency has even been considered in playing a role in the development of Alzheimer's disease [3][4][5][6][7].The vitamin B 12 cofactor contains a cobalt atom surrounded by an equatorial corrin ring. Covalently linked to the central atom is a dimethylbenzimidazole that occupies one of the axial coordination positions. The opposite coordinate is available for several ligands in bio-medium or in solution; however, known biologically active structures containing adenosyl-or methyl have been considered most often (Figure 1).

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Computational Insights into the Mechanism of Radical Generation in B₁₂-Dependent Methylmalonyl-CoA Mutase

Cited by 77 publications

References 46 publications

Transition States in a Protein Environment − ONIOM QM:MM Modeling of Isopenicillin N Synthesis

Transition States in a Protein Environment − ONIOM QM:MM Modeling of Isopenicillin N Synthesis

A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes

The Nature of the Co-C Bond Cleavage Processes in Methylcob(II)Alamin and Adenosylcob(III)Alamin

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Computational Insights into the Mechanism of Radical Generation in B12-Dependent Methylmalonyl-CoA Mutase

Cited by 77 publications

References 46 publications

Transition States in a Protein Environment − ONIOM QM:MM Modeling of Isopenicillin N Synthesis

Transition States in a Protein Environment − ONIOM QM:MM Modeling of Isopenicillin N Synthesis

A new paradigm for electrostatic catalysis of radical reactions in vitamin B 12 enzymes

The Nature of the Co-C Bond Cleavage Processes in Methylcob(II)Alamin and Adenosylcob(III)Alamin

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Computational Insights into the Mechanism of Radical Generation in B₁₂-Dependent Methylmalonyl-CoA Mutase

A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes