Tag Archives: allosteric effects

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.


Remember entropy?

Organic chemists have a far better intuitive feel for entropy than most chemists. Condensations such as the Diels Alder reaction decrease it, as does ring closure. However, when you get to small ligands binding proteins, everything seems to be about enthalpy. Although binding energy is always talked about, mentally it appears to be enthalpy (H) rather than Gibbs free energy (F).

A recent fascinating editorial and paper [ Proc. Natl. Acad. Sci. vol. 114 pp. 4278 – 4280, 4424 – 4429 ’17 ]shows how the evolution has used entropy to determine when a protein (CzrA) binds to DNA and when it doesn’t. As usual, advances in technology permit us to see this (e.g. multidimensional heteronuclear nuclear magnetic resonance). This allows us to determine the motion of side chains (methyl groups), backbones etc. etc. When CzrA binds to DNA methyl side chains on the protein move more, increasing entropy (deltaS) and as well all know the Gibbs free energy of reaction (deltaF) isn’t just enthalpy (deltaH) but deltaH – TdeltaS, so an increase in deltaS pushes deltaF lower meaning the reaction proceeds in that direction.

Binding of Zinc redistributes these side chain motion so that entropy decreases, and the protein moves off DNA. The authors call this dynamics driven allostery. The fascinating thing, is that this may happen without any conformational change of CzrA.

I’m not sure that molecular dynamics simulations are good enough to pick this up. Fortunately newer NMR techniques can measure it. Just another complication for the hapless drug chemist thinking about protein ligand interactions.