Wednesday, July 8, 2009

Quantum biology? Tunneling in enzymes

Over the past two decades the possibility of quantum tunneling of protons in enzymes
has attracted considerable attention. (See for example a piece in Nature by Philip Ball (my favourite science writer) or the proceedings of a meeting at the Royal Society

The observed large kinetic isotope effects and their temperature dependence are inconsistent with semi-classical transition state theory, whereby the chemical reaction occurs via thermal activation over an energy barrier. These discrepancies have been interpreted as evidence for the presence of tunneling. However, it should be stressed that this evidence is indirect, being based on the values of fitting parameters for Arrhenius plots where the absolute temperature only varies by about ten per cent.
In contrast, for chemical reactions involving simpler organic molecules, such as benzoic acid much more definitive signatures of proton tunneling have been observed. These include a temperature independent rate at low temperatures and tunnel splitting of the ground
state energy.
Key questions that need to be answered include:
  • Can all the known experimental results be explained without tunneling?
  • To what extent is it necessary to go beyond the traditional semi-classical transition state theory to explain the observed kinetic isotope effects of enzymes?
  • If tunneling does occur, is it actually important for the function of the enzyme?
  • Have enzymes evolved in a manner that enhances the contribution of tunneling?
There are currently a wide range of views on the answers to these questions.
For example, a review in Science, How Enzymes Work: Analysis by Modern Rate Theory and Computer Simulations by Mireia Garcia-Viloca, Jiali Gao, Martin Karplus, and Donald G. Truhlar states that,
``the entire and sole source of the catalytic power of enzymes is due to the lowering of the free energy of activation and any increase in the generalized transmission co-efficient, as compared to that of the uncatalyzed reaction."
Villa and Warshel state that,
``the most important contribution to catalysis comes from the reduction of the activation free energy by electrostatic effects ... the popular proposal that enzymes catalyze reactions by special dynamical effects is not supported by a consistent simulation study ... the interpretation of recent experiments as evidence for dynamical contributions to catalysis is unjustified.''
In contrast, Klinman and collaborators stated in a 1999 Nature paper that,
``Our present findings on hydrogen transfer under physiological conditions cannot be explained without invoking both quantum mechanics and enzyme dynamics.''
In a paper that focused on simulations Schwartz and collaborators express a similar view,
``The action of the enzyme in speeding the chemical reaction, however, is postulated to be intimately connected to the directed vibrational motion identified in this paper. Thus, it appears that evolution has designed the protein matrix of an enzyme not just to hold substrates or stabilize transition state formation, but rather to channel energy in a specific chemically relevant direction.''
I align myself with the skeptics in a paper I am working on..... more to come..

9 comments:

  1. Again, I am working backwards (following on from my comment to the post that comes 4 posts later).

    Again, there is probably a devil lying in the details of transition-state theory here, and it may be at a fairly basic level. Perhaps, there is a problem with separability of the reactive and nonreactive modes here at the transition state. Any interdependence would 'mix' the state of the system (presumed to be pure if separability holds). Proteins are strange beasts, and are not 3-dimensional (see Chowdry/Gruebele contribution the current J. Phys. Chem. A ASAP alerts: "Molecules: What Kind of a Bag of Atoms?").

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  2. Enzyme molecules contain a special pocket called an active site, which contain amino acid from different parts of the polypeptide chains that create a three dimensional surface complementary to the substrate, just as a key fits into a lock. Substrates initially bind to the active site by non-covalent interactions, enzyme catalytic modes

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