Howlers > Uncharged amino acids

Zwitterions

This page discusses the zwitterionic nature of amino acids and is one of a series that discuss common errors in current textbooks of biochemistry.


All of the pages in this series are in urgent need of updating. The biochemical principles have not changed, of course, but textbooks have: some of those that were current when I first prepared these pages in 2000 have appeared in new editions, and others have ceased to be widely used. New books have appeared that are not discussed. Unfortunately I do not have easy access to any of the commonly used textbooks, as I work in a research (not teaching) environment in a country where English is not the everyday working language. I could buy them, of course, but that would represent rather a large investment for the sake of a few web pages.

Accordingly I should be grateful if someone would collaborate with me in the revision. If you have access to all of the textbooks published in English in the past ten years (say 1996 or later) that are commonly used for teaching biochemistry, and if you would like to help, please contact me at acornish@ibsm.cnrs-mrs.fr.

The problem

This problem is far less common than it used to be, giving hope that at least some common textbook errors can be corrected if enough people are vigilant. Nonetheless, one still finds it in a diluted form in modern textbooks.

Thirty years or more ago, many books would begin by defining the structure of an amino acid as H2N-CHR-CO2H. For example, Mahler and Cordes (1966) in Biological Chemistry give NH2—CHR—COOH as the general structure of an amino acid on p. 9, and further down the same page they illustrate the stereochemical structure of alanine in this style. The next five pages are taken up with a long table listing all the common amino acids and some of the less common ones in the same way.

The better books (of which Mahler and Cordes was certainly the champion) would then mention (on p. 15 in Mahler and Cordes) that the true structure at neutral pH was H3N+-CHR-CO2- but would then spoil it (effectively saying that they didn't believe a word of what they had just said, or at least, didn't understand it) by reverting to wrong structures for the rest of the book: in Mahler and Cordes we are back to wrong structures as soon as p. 17, and they continue for most of the rest of the book, though occasionally (e.g. p. 681) zwitterionic structures are shown.

I do not know of a modern book that follows the full sequence, but Campbell starts by defining the structures wrongly (p. 72 and 83), corrects herself on pp. 85–86 (though without noticing the implication that the table on p. 83 is wrong) and gets them mainly right in the rest of the book.

As a more confused example, Garrett and Grisham give a correct account (with a correct explanation) on p. 56, but in their table on pp. 58–59 they show all the structures (apart from that of proline, which shows the traditional howler) in the forms that exist at low pH, i.e. with protonated -CO2H as well as (correctly) protonated -NH3+. Elsewhere in the book they sometimes get it right (e.g. on p. 833), and sometimes wrong (e.g. on p. 107), where iodoacetate (the name of the anion, not the acid) is said to be ICH2COOH.

A different kind of confusion arises in these sentences, from Mathews, van Holde and Ahern (pp. 127–128), which relates to a drawing showing the incorrect uncharged structure:

However, this structure, although chemically correct, ignores the conditions in vivo. As pointed out in Chapter 2, most biochemistry occurs in the physiological pH range near neutrality.

from Stryer: (p. 19)

Amino acids in solution at neutral pH are predominantly dipolar ions (or zwitterions) rather than un-ionized molecules.

and from Lehninger, Nelson and Cox (p. 114)

The nonionic form does not occur in significant amounts in aqueous solutions.

The last two of these are correct as far as they go, but they wrongly imply limitations on the generality of the zwitterionic structure of amino acids. In fact the principles underlying this structure have nothing to do with conditions in vivo, and the uncharged structure is chemically incorrect. Moreover, it is not just from neutral solution that the un-ionized molecule is absent. It is non-existent for practical conditions under all other conditions as well, including the solid: the reason why crystalline glycine looks like a salt is that it is a salt.

Notice that the principles apply to all -NH3+ and -CO2- groups, not just those that occur in amino acids, and that exceptions are possible if one is considering extreme conditions. For example, if one is discussing pepsin action in the mamalian stomach it is perfectly correct to write the carboxylic acid group as -CO2H.

Another point is that the names of the amino acids refer to the structures of the fictitious uncharged molecules, and a case can be made for showing them with these structures in a purely nomenclatural context, provided that it is made very clear at the same time that these are not the real structures that exist in solution under neutral conditions. Personally I dislike this practice even then but I do not find it intolerable.

Why does it matter?

Glycine (for example) is a white crystalline solid that both looks like a salt and behaves like a salt. Its properties bear little resemblance to those of a toxic gas like methylamine or a fuming liquid like acetic acid. It is not easy for students to remember that it is a salt, or to understand why it looks and behaves like one, if they are taught that its structure contains the same functional groups as methylamine and acetic acid. In discussing the properties of proteins it is important to understand that their acidic properties are due to very weakly acidic groups, such as the ammonio group -NH3+, and not (except in very rare cases such as pepsin catalysis) to much more strongly acidic groups like -CO2H, which does not exist under neutral conditions; their basic properties are likewise due to very weakly basic groups, such as the carboxylate anion, -CO2-.

Textbook checklist

Abeles, Frey and Jencks OK Brief but correct Inside cover and p. 41
Campbell Poor Mainly correct apart from first mention pp. 72–73
Garrett and Grisham Bad Amino group usually correct, carboxylate group usually incorrect; proline completely wrong pp. 58–59
Horton et al. OK No problems noted pp. 54–57
Lehninger, Nelson and Cox Poor Correct apart from implication that zwitterion occurs only in solution pp. 114–115
McKee and McKee OK Correct presentation p. 79
Mathews, van Holde and Ahern Poor Correct apart from first mention pp. 127–129
Stryer Poor Correct apart from first mention p. 19
Voet and Voet OK Correct presentation pp. 57–59
Zubay OK Correct presentation pp. 48–53

Other common errors in textbooks

List of books considered