Thursday, July 9, 2009

Multiple hypotheses in action (speed up the rate of doing science)

I am excited. This post ties together a previous post about doing science as opposed to just publishing papers and the controversy about the role of dynamics and quantum tunneling of protons in enzymes. I just reread a beautiful paper, entitled, "A Compelling Experimental Test of the Hypothesis That Enzymes Have Evolved To Enhance Quantum Mechanical Tunneling in Hydrogen Transfer Reactions", by Doll and Finke. It contains the figure below which clearly illustrates its goal, to test Kliman's hypothesis:
“The optimization of enzyme catalysis may entail the evolutionary implementation of chemical strategies that increase the probability of tunneling and thereby accelerate the reaction rate
Furthermore, the authors formulate three alternative hypotheses.


Read the abstract. It is brilliant.

Through some very clever synthetic chemistry they make several molecules that undergo the same hydrogen abstraction reaction as in the enzyme. They then compare reaction rates and kinetic isotope effects.

I will leave you to read the conclusion in the abstract...

Later I will present an alternative hypothesis which is also consistent with the data: the only role of quantum effects is the interplay of quantum and thermal fluctuations at the transition state.

3 comments:

  1. Very tricky - you are implying that a 'transition state' in the normal sense exists for proton transfer reactions. I am not sure that I agree with this...

    The Born-Oppenheimer perturbation parameter (m_elec/m_nuc)**1/4 is greatest for the proton, suggesting that proton modes should break the BO approximation more readily than for heavier atoms. (BTW, This should have a signature, namely anomalous rate dependence on deuterium substitution - something I've mentioned in COPE meetings but which may not have been noticed at the time.) However, the invocation of a 'transition state' in the usual chemical sense depends very intimately on the BO approximation, and it is not clear what is meant by 'transition state' if the approximation fails...

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  2. A of this is within the context of the BO approximation. It certainly breaks down more readily for protons but all of these discussions assume BO. I am not convinced this is wrong. There are big kinetic isotope effects (i.e., from deuterium substitution). But, Jacques and I can explain all the data from a quantum transition state picture, contrary to what most people in the field claim.

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  3. OK, maybe I'm confusing myself. I guess what I'm really getting at is that a better picture might be to build the proton modes into the BO approximation. Of course this is very dicey, but the validity would have to be judged on how the energies of the actual normal modes fall in the system under consideration. If there is a gap in the density of states of modes which are mixtures of proton motion, then maybe one can talk about an approximation where some of the proton modes are built into the Schrodinger Equation which gives the eigenvalues defining the surface for all of the slower modes. I suppose this is along the lines of what Hammes-Schiffer does.

    There is a good paper by Miller that is relevant here.* I suppose the point here is that proton transfer lies at an important boundary where limits corresponding to different reaction paths which are "marginals" of a 2-D surface begin to break down.

    * Tucker Carrington and Miller. Reaction surface description of intramolecular hydrogen atom transfer in malonaldehyde. The Journal of Chemical Physics (1986) vol. 84 (8) pp. 4364-4370

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