The incredible chemical intelligence of an inanimate enzyme

God, I love organic chemistry.  Here’s why.  A recent Nature paper [ vol. 573 pp. 609 – 613 ’19 ] shows that an enzyme uses a Newton’s cradle to shuttle an allosteric effect some 25 Angstroms between two catalytic centers.  I’d never heard of Newton’s cradle, but you’ll recognize it from the picture when you follow this link — https://en.wikipedia.org/wiki/Newton%27s_cradle.  It is a device used to show that most classic example of classical (e.g. nonQuantum) physics — the conservation of momentum.

This despite Feynman’s statement in the Feynman Lectures on Physics Vol I. p 12 – 6 “Molecular forces have never been satisfactorily explained on a basis of classical physics” it takes quantum mechanics to understand them fully.”  True but chemists think of reactions in terms of classic physics all the time (harmonic oscillators as bond models, billiard ball collections hitting each other as in SN2).

To understand what is going on, you must understand the low barrier hydrogen bond. [ Proc. Natl. Acad. Sci. vol. 95 pp. 12799 – 12802 ’98 ] which is a type of hydrogen bond postulated to occur in enzymes, in which the potential barrier to shifting the hydrogen from one nucleophile (oxygen or nitrogen) in the bond to another is quite low (2 Kcal/mole). The nucleophiles are closer together than they usually are ( e. g. the interatomic distance between the two heteroatoms is smaller than the sum of their van-der-Waals radii (≤ 2.55 Å for O–O pairs; ≤ 2.65 Å for O–N pairs), and the hydrogen is essentially covalently bonded to both. This makes the hydrogen bonds quite strong (10 – 20 Kcal/mole). They think that such bonds stabilize intermediates in enzymatic reactions (such as that formed by the catalytic triad of a serine protease).

Regard the low barrier hydrogen bond as what glues the balls together in the Wiki picture.

The enzyme described in the paper (transketolase) uses a chain of low barrier hydrogen bonds as a communication channel between the two remote (25 Angstroms away) active sites in the obligate functional dimers.

The still pictures have to be seen to be believed.  I can’t wait for the movie.

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Comments

  • Ashutosh  On October 4, 2019 at 1:01 pm

    There was an entire, fascinating debate about low-barrier hydrogen bonds and whether they even exist in the 90s which was reminiscent of the non-classical ion debate between Brown and Winstein. As usual, there was no definitive answer, but the experiments and calculations inspired new thinking. The main question was whether these hydrogen bonds could possible have energies of up to 20 kcal/mol, numbers which are usually associated with covalent bonds. The problem, as always, is that the answer depends on the method.

  • luysii  On October 4, 2019 at 1:54 pm

    Fair enough. But the paper contains the following substantial evidence for the existence of the Low Barrier Hydrogen Bond (LBHB).

    “Structural analysis of human transketolase with a covalent substrate–ThDP intermediate at a resolution of 0.97 Å enabled us to assign the positions of hydrogen atoms at the thiamine cofactor and in the communication channel (Fig. 1b). The electron-density maps suggest that E366′ and E160 share a proton (Fig. 1b): the location of the hydrogen atom almost exactly halfway between the two carboxylate side chains” Also –“The short O–O distance of 2.56 Å (Fig. 1c), is indicative of an LBHB between the two glutamates”

  • Ashutosh  On October 6, 2019 at 10:20 pm

    Have they taken multiple side chain conformations into account? There was some sound debunking of a recent MIT paper on short hydrogen bonds that ignored multiple conformations which when taken into account and averaged over led to longer distances (https://pubs.acs.org/doi/full/10.1021/acs.jcim.9b00473)

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