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I understand that the imidazole ring in histidine is aromatic. I also realize that it retains its aromaticity when protonated. I am wondering why this is not mentioned at all in basic text books such as Lehninger? Also, across the web there are a number of places claiming that histidine isn't aromatic in all cases. Another reason I am a little confused is, if protonation doesn't alter the aromatic nature, then why is histidine such a weak base?

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This is one of my favorite charts demonstrating the complexity of amino acid properties:

Amino Acid Properties http://www.jalview.org/help/html/misc/aaproperties.html

Histidine is probably the most complicated amino acid in this regard (just compare how many circles it falls into). But don't undersell cysteine and methionine: those sulfurs exhibit some surprising behavior, especially when coordinated properly. Cysteine, of course, forms disulfide bonds, with methionine occasionally functioning as a methyltransferase.

Biochemistry textbooks make some oversimplifications because presenting the full messiness of these classifications is pretty confusing. Lehninger is the worst about this, especially when presenting math. Voet and Voet is probably the most reliable about presenting this complexity. I still think Lehninger is a better teaching textbook overall (I was first taught biochemistry from the 3rd edition), but I also recall spending a week being confused about a topic before someone pointed me at V and V and I realized Lehninger was oversimplified to the point of being wrong, in that case.

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  • $\begingroup$ Diagram is nice and informative +1 :) $\endgroup$
    – Dexter
    Nov 6, 2015 at 6:35
  • $\begingroup$ @Dexter I also like the diagram. Do you agree these are improvements? 1. "Tiny", rather than "tiny". 2. Instead of blue, green, and grey as the main colors and blue (twice, which is confusing) and brown (which is so dark as to make reading the black print difficult) that are hard to distinguish, howabout the big three being the light primaries ie red, green, and blue? Then the overlaps would be more clear (and have intrinsic interest). 3. How about distinguishing medium/big/huge? As it is leucine and tryptophan are lumped together. 4. Removing the "Charged" ellipse, since it adds nothing. $\endgroup$ Mar 9, 2023 at 6:50
  • $\begingroup$ Contd. 5. How about representing size by position, e.g. distance from the center of the "SMALL" oval, or from the center of the diagram as a whole? That way, the ranking by size could be made clear, and even the actual magnitudes of the size. 6. How about something more precise than "small" and "tiny". Does it refer to volume, mass, number of atoms, or something else? $\endgroup$ Mar 9, 2023 at 6:55
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I am wondering why it is not mentioned at all in basic text books such as Lehninger?

Books are not flawless.

Another reason I am a little confused is, if protonation doesn't harm the aromatic nature, then why is histidine such a weak base?

Pyrroles have a weak basicity because of delocalization of the electron lone pair of nitrogen. It is the lone pair of nitrogen, in amines, which gives it basicity (Check Lewis bases and acids) .

In imidazole, the other nitrogen (N-2) has a free lone pair and does contribute to its basicity. As you pointed out before, imidazolium is a stable moiety and imidazole is a much stronger base than pyridine, although it is a weaker (pKb ≃ 7) base than lysine (pKb ≃ 10.5) and arginine (pKb ≃ 12.48).

Imines are generally weaker bases than amines because the sp2 hybridization of the former gives them a more s-like character; this causes the lone pair to be held more tightly to the nucleus thereby reducing the basicity. Also, the C-N(2)-C angle is constrained (small) because of the planar ring. This again leads to a more s-like character.

The strong basicity of arginine is because of the guanidium group.

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The imidazole ring in histidine is indeed aromatic. But "aromatic amino acid" does not usually mean "amino acid with an aromatic ring". Rather, it indicates one or more particular chemical properties, such as high absorption at 280nm, or, better, its metabolic pathway.

Histidine as a stand-alone amino acid is a weak base, but this is mainly due to the amino group and acid group that every amino acid has. The imidazole ring itself has a neutral pKa.

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  • $\begingroup$ I was referring to the basicity of the side chain itself. Why is its pKa neutral? $\endgroup$
    – Alexandra
    May 6, 2013 at 11:46
  • $\begingroup$ i dont think there is a term called neutral pKa. pKa of water is ~15.7. pKa of imidazole is ~14 which makes it slightly better acid compared to water but poorer acid compared to carboxylic acids. $\endgroup$
    – WYSIWYG
    May 6, 2013 at 15:46
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    $\begingroup$ @WYSIWYG: I was referring to the deprotonation of the acid conjugate, physiologically more relevant. pKa≃7. I agree that 'neutral pKa' is a misnomer. $\endgroup$
    – biozic
    May 6, 2013 at 17:58
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The reason why it's mostly referred to as basic is because the non-protonated nitrogen in the ring has a lone pair that it actively donates in several biochemical reactions. Lone pair donator = Lewis base

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    $\begingroup$ Hi and welcome to Bio.SE! This is more of a comment on the protonation rather than the aromaticity. Once you get more reputation you'll be able to make comments. If you want to expand your answer, see these tips on writing a good answer. $\endgroup$
    – James
    Oct 28, 2019 at 10:40
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Consider it as an amino acid with "pro-chiral auxiliary" properties instead of broadening the entire molecule as aromatic.

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    $\begingroup$ Welcome to SE Biology. You may not have noticed that this badly confused question was posted almost ten years ago, and the poster has not been on the site in the last eight. If you think that the description "pro-chiral auxiliary" is an important general contribution to the topic, then you need to explain what it means. I am a native English speaker, have a degree in Chemistry, and have taught biochemistry for many years. The phrase means nothing to me. $\endgroup$
    – David
    Jun 17, 2022 at 16:45

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