Tunnelling, hydrogen

Whilst kinetic isotope effects in excess of the above semiclassical theoretical maxima are an indication of tunnelling, they can in principle have other causes (for example, if the approximation of lumping the rest of the molecule into a notional atom X is abandoned, then bending frequencies as well as stretching frequencies have to be considered and maximal semi-classical isotope effects double). Other evidence is therefore required before tunnelling can be 

It has been suggested that protein motions in enzyme-substrate complexes play a catalytic role by transiently altering the shapes of energy barriers to permit tunnelling ( vibrationahy assisted tunnelling ) but the experimental basis for this appears insecure.  

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The important criterion thus becomes the ability of the enzyme to distort and thereby reduce barrier width, and not stabilisation of the transition state with concomitant reduction in barrier height (activation energy). We now describe theoretical approaches to enzymatic catalysis that have led to the development of dynamic barrier (width) tunneUing theories for hydrogen transfer. Indeed, enzymatic hydrogen tunnelling can be treated conceptually in a similar way to the well-established quantum theories for electron transfer in proteins. 

Transition state theory and corrections for hydrogen tunnelling... 

Relationships between reaction rate and temperature can thus be used to detect non-classical behaviour in enzymes. Non-classical values of the preexponential factor ratio (H D i 1) and difference in apparent activation energy (>5.4kJmoRi) have been the criteria used to demonstrate hydrogen tunnelling in the enzymes mentioned above. A major prediction from this static barrier (transition state theory-like) plot is that tunnelling becomes more prominent as the apparent activation energy decreases. This holds for the enzymes listed above, but the correlation breaks down for enzymes... 

Kohen, A.. Klinman, J. 1999 Hydrogen tunneling in biology. Chem. Biol. 6, R191-R198. 

Al-Soufi W, Grellmann KH, Nickel B (1991) Keto-enol tautomerization of 2-(2 -hydroxy-phenyl)benzoxazole and 2-(2 -hydroxy-4 -methylphenyl) benzoxazole in the triplet state hydrogen tunneling and isotope effects. 1. Transient absorption kinetics. J Phys Chem 95 10503-10509... 

Kawai H, Yeo YK, Saeys M, Joachim C (2010) Conductance decay of a surface hydrogen tunneling junction fabricated along a Si(001)-(2xl)-H atomic wire. Phys Rev B 81 195316... 

This is a subject in which the role of sophisticated theoretical work has been especially crucial aheady, and its importance continues to grow. The most controversial aspect of the subject is the question of whether and how protein vibrations are directly linked to the catalysis of hydrogen tunneling by enzymes. The full nature and value of the theoretical work is not covered in the present article, nor are the evidence and concepts that underlie proposals for the involvement of protein dynamics. It is our intention to follow the present article with a later treatment of the theoretical contributions and the dynamical questions. 

It may have been the dramatic 1964 publication of E.S. Lewis and L. Funderburk that forced the question of hydrogen tunneling in complex solution reactions near room temperature into the consciousness of a larger scientific public, particularly in physical-organic chemistry. This article presented isotope effects for proton abstraction from 2-nitropropane by a series of substituted pyridines, and the values rose sharply as the degree of steric hindrance to the reaction increased (Fig. 1). AU the observed H/D isotope effects, from 9.6 to 24, were larger than expected from the simplest version of the so-called semiclassical theory of isotope effects (Fig. 2). 

Fig. 3 Hydrogen tunneling according to the Bell model can generate anomalous isotopic Arrhenius parameters. A semiclassical model with = 0 (thus Ah = A ) and...

For further important work on this and related concepts, see Rucker, J. and Kliman, J.P. (1999). Computational study of tunneling and coupled motion in alcohol dehydrogenase-catalyzed reactions Implication for measured hydrogen and carbon isotope effects. J. Am. Chem. Soc. 121, 1997 -2006, and Kohen, A. and Jensen, J.H. (2002). Boundary conditions for the Swain-Schaad relationship as a criterion for hydrogen tunneling. J. Am. Chem. Soc. April 17, 124(15), 3858-3864. 

Agrawal, N., Hong, B., Mihai, C. and Kohen, A. (2004). Vibrationally enhanced hydrogen tunneling in the Escherichia coli thymidylate synthase catalyzed reaction. Biochemistry 43, 1998-2006... 

Maglia, G. and AUemann, R.K. (2003). Evidence for environmentally coupled hydrogen tunneling during dihydrofolate reductase catalysis. J. Am. Chem. Soc. 125, 13372-13373... 

Tsai, S. and Klinman, J.P. (2001). Probes of hydrogen tunneling with horse Uver alcohol dehydrogenase at subzero temperatures. Biochemistry 40, 2303-2311... 

Chin, J.K. and Klinman, J.P. (2000). Probes of a role for remote binding interactions on hydrogen tunneling in the horse liver alcohol dehydrogenase reaction. Biochemistry 39, 1278-1284... 

Karsten, W.E., Hwang, C.C. and Cook, P.F. (1999). Alpha-secondary tritium kinetic isotope effects indicate hydrogen tunneling and coupled motion occur in the oxidation of L-malate by NAD-malic enzyme. Biochemistry 38, 4398-4402... 

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