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I am an enzymologist and I would like to check whether the consensus of how enzymes tell thioethers from hydrocarbons on substrates is a fact or fiction. So are any of these wrong?

  1. S–π interactions are the sole discriminant (in enzymes at least)
  2. They have the same dipole
  3. They are the same size
  4. A thioether and a hydrocarbon have the same angle

From what I can tell...
Point #1 is not really in question: even if it does not account for much, aromatic residues are often found with thiols and thioethers (1/3 of protein have a methione involved in a S–π interaction). From what I can tell of point #2, 3.55 vs. 3.58 units in electronegativity (ref. wikipedia: electronegativity) won't make a difference. From point #3, while, yes, sulfide is 360 pm and methane is 380 pm (ref. wikipedia: kinetic diameter), but the former is R-S-R, R-CH2-R, so it might be different.

I am not saying they are very different: thialysine (thioether) is a toxic analog of lysine (alkane) and norleucine (alkane) of methionine (thioether; toxic for SAM usage only) due this reason. But nature has evolved to discern similar compounds.

An example, cystathionine (pictured below) is a thioether of cysteine + homoserine or homocysteine + serine (both routes exist) and one enzyme (cystathionine beta-lyase, CβL) can bind the amine on the shorter side, deprotonate the α-carbon and eliminate the thiol (homocysteine) and release the imine (hydrolysed to pyruvate), while a different enzyme (cystathione gamma-lyase, CγL) acts on the other (cysteine and ketobutyrate). The two enzymes do not catalyse both reacts as it would be wasteful (not much just a ATP>AMP). The evolution from one to the other has not be published, but from what I can tell S–π interaction is the driving force. AFAIK, the closest literature to this on cystathionine elimination is my own paper, so I know there is no answer there. cystathionine

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  • $\begingroup$ This is very interesting, but I can't find the question in there. $\endgroup$ – Lighthart May 13 '16 at 20:14
  • $\begingroup$ I meant to ask whether any of the four points were wrong. I put an example at the bottom to emphasize that they are different, so I must be wrong somewhere. $\endgroup$ – Matteo Ferla May 13 '16 at 20:28
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I just realised that I got the dipole business utterly wrong as sulfur has two lone pairs.
I checked dimethyl sulfide, propane and dimethyl ether and was surprised how differently they behaved. The former has a total dipole moment of 1.5 D ref, while the second near zero (0.1 D) as expected from a non-polar molecule, while the last has 1.3 D.
Whereas there is only a 0.03 difference in electronegativity between C and S (vs. .89), the geometry is different, which I did not know about. Wikipedia on says:

  • thioether article: "C–S–C angle approaching 90°. The C–S bonds are about 180 pm."
  • ether article: "C–O–C linkage defined by a bond angle of about 110° and C–O distances of about 140 pm".
  • alkane article: "154 [pm] for a C–C bond [and] with an angle of 109.47° between them."

So the side chain of methionine should actually be able to hydrogen bond with stuff (not electrostatically, but dispersively). So I was surprised to find papers I had not found prior (ex1, ex2).

S-π are probably the strongest force nevertheless (the bond has an enthalpy of 2.6, 1.1 or 0.7 kcal mol-1 depending on the angleref, which is comparable to N−H···:O hydrogen bond (1.9 kcal mol-1))

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