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I saw the chart in this post Histidine aromaticity. Since I'm not allowed to comment and post a question instead of an answer, I have to ask my question in a separate thread.

How can histidine be classified both as positively charged and hydrophobic?

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  • $\begingroup$ Histidine is not hydrophobic $\endgroup$ – WYSIWYG Oct 31 '14 at 8:45
  • $\begingroup$ BTW: You are going the right way here - asking new questions in the answer (or comment) section under other questions is not well liked. $\endgroup$ – Chris Oct 31 '14 at 9:09
  • $\begingroup$ Charged or not, histidine is aromatic because it fulfills all of the aromaticity criteria: 1.The molecule is cyclic. 2. The molecule is planar. 3. The molecule is fully conjugated (p orbitals at every atom in the ring). 4. The molecule has 4n+2 π electrons, where n is a positive integer. $\endgroup$ – Stefan Jan 31 '18 at 19:31
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As @wysiwig stated, Histidine is not hydrophobic. Depending on the pH different parts of the molecule can carry charges, see the image below (from here):

enter image description here

The nitrogen atoms can be protonated in an acidic environment, the carboxylgroup will loose it proton in a basic environment. All these forms are transferred into each other, when the pH changes.

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As @Chris says, the charge depends on the pH: when the pH is different from the pH(I) of the molecule, this one is charged.(Take a look at this). Anyway, talking about Hys, its pH(I) is 7.47 (here), so at a pH below its pI, the Histidine carry a net positive charge, otherwise it can be also in a netrual form. Obviously it's all a matter of equilibrium!

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  • $\begingroup$ Yeah, I think so... $\endgroup$ – Serena Nov 1 '14 at 15:24
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As a matter of fact, the chart above is not wrong; it is quite correct. Indeed, histidine can carry a net positive charge, but when unprotonated, i.e. in a charge-neutral state, its aromatic π-system (belonging to the imidazole moiety) can behave like a hydrophobic group, e.g. it can become involved in π-stacking (aka CH-π) interactions. In the 2RS2 NMR structure, for example, HIS83 is δ-protonated and appears to be behaving like a typical hydrophobic residue: it is buried below the protein surface, stacked against several aromatic residues and packed along with several aliphatic ones; it is shielded from solvent by polar and charged residues.

enter image description here

2H95 is a very interesting structure where we see four ε-protonated histidines stack against tryptophans, as well as pack against aliphatic side chains, forming a transmembrane proton channel. The histidines appear to be involved in hydrohobic interactions, and, notably, at the same time form the inner surface of the channel.

enter image description here

Conversely, in the 2NBJ NMR structure, we see HIS56 behaving like a polar amino acid - its (doubly protonated) side chain is involved in hydrogen bonding to the backbone oxygen of a DNA fragment, as well as to a backbone oxygen atom from the protein. Moreover, in the same structure, HIS16 is doubly protonated and solvent exposed, likely interacting with water and contributing to solvation, in stark contrast to HIS83 in the 2RS2 structure, which is monoprotonated and buried in the hydrophobic interior of the protein.

enter image description here

Histidine's pKa can easily be perturbed by its surroundings, e.g. by the surrounding residues in an enzyme active site, which makes it highly functionally versatile, one of the manifestations of its functional and chemical versatility being its ability to behave both as a polar/charged amino acid, as well as a hydrophobic residue; this is the reason histidine is often found in functional sites in proteins, e.g. enzyme active centers.

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    $\begingroup$ You make assertions which may or may not be right, but you provide no third-party support for your answer. Although it has been accepted, the poster has no basis on which to judge it correct. What you need to do is to edit your answer to provide examples of proteins (with links) in which histidine is clearly uncharged and involved in π-stacking interactions. Then I and others can go to the links and decide whether to vote your answer up or down. $\endgroup$ – David Jan 29 '18 at 13:41
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    $\begingroup$ I look forward to seeing that. It will enhance the standards of this site. Take your time. $\endgroup$ – David Jan 29 '18 at 14:49
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    $\begingroup$ I've already added the reference to the answer. $\endgroup$ – Stefan Jan 29 '18 at 14:50
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    $\begingroup$ I've read the paper and it seems to me to relate only to theoretical calculation of π-π interactions, assuming they exist, with the conclusion that they are relatively weak compared with other His interactions. What is lacking in the paper is a single example of a π-π interaction in a protein. I am familiar with PDB, but do not see how to perform a search for π-π interactions involving His to quickly return examples. (A slow search by eyeballing, I understand.) I am not saying you are wrong, but I do not think you have proven your case. At the moment it seems just hand waving. $\endgroup$ – David Jan 30 '18 at 12:06
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    $\begingroup$ Thanks. Very good. The proton channel seems intriguing, although I'm not actually a protein chemist. Must ask a colleague about it. (If you add any more pics, I'd scale them down a little for ease of reading your whole answer.) $\endgroup$ – David Jan 31 '18 at 11:45

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