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. 2007 Jun 26;104(26):10774-9.
doi: 10.1073/pnas.0702188104. Epub 2007 Jun 20.

Coupling of hydrogenic tunneling to active-site motion in the hydrogen radical transfer catalyzed by a coenzyme B12-dependent mutase

Agnieszka Dybala-Defratyka  1 , Piotr Paneth, Ruma Banerjee, Donald G Truhlar
Affiliations

Coupling of hydrogenic tunneling to active-site motion in the hydrogen radical transfer catalyzed by a coenzyme B12-dependent mutase

Agnieszka Dybala-Defratyka et al. Proc Natl Acad Sci U S A. .

Abstract

Hydrogen transfer reactions catalyzed by coenzyme B(12)-dependent methylmalonyl-CoA mutase have very large kinetic isotope effects, indicating that they proceed by a highly quantal tunneling mechanism. We explain the kinetic isotope effect by using a combined quantum mechanical/molecular mechanical potential and semiclassical quantum dynamics calculations. Multidimensional tunneling increases the magnitude of the calculated intrinsic hydrogen kinetic isotope effect by a factor of 3.6 from 14 to 51, in excellent agreement with experimental results. These calculations confirm that tunneling contributions can be large enough to explain even a kinetic isotope effect >50, not because the barrier is unusually thin but because corner-cutting tunneling decreases the distance over which the system tunnels without a comparable increase in either the effective potential barrier or the effective mass for tunneling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1.
Scheme 1.
Hydrogen atom transfer from substrate to cofactor in the mutase-catalyzed reaction.
Fig. 1.
Fig. 1.
Schematic illustration of a hypothetical corner-cutting tunneling path. Two generalized coordinates are denoted x and y. The MEP (solid curve) leads from the reactant valley through a saddle point (black dot) to the product valley. The dashed line shows a possible corner-cutting path; this path involves a higher barrier than the MEP because it does not pass through the saddle point, but it is shorter.
Fig. 2.
Fig. 2.
Vibrationally adiabatic ground-state potential-energy curve (VaG) as a function of the reaction coordinate for the H case (a) and the D case (b). In each case, the dashed horizontal line denotes the representative tunneling energy.
Fig. 3.
Fig. 3.
Two-dimensional representations of the minimum-energy path (solid line) and representative tunneling path (dashed line) for H transfer. RaH is the distance from the acceptor (a) carbon to the transferred H, and RdH is the distance from the donor (d) carbon to the transferred H.
Fig. 4.
Fig. 4.
Two-dimensional representations of the minimum-energy path (solid line) and representative tunneling path (dashed line) for D transfer. RaD is the distance from the acceptor (a) carbon to the transferred D, and RdD is the distance from the donor (d) carbon to the transferred D.
Fig. 5.
Fig. 5.
The setup for the QM/MM calculation. The water molecules are shown in blue, the protein is in green, and the rest is depicted in black.
See this image and copyright information in PMC

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