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The conjugate acid (protonated form) of the [[imidazole]] [[side chain]] in histidine has a [[Acid dissociation constant|p''K''<sub>a</sub>]] of approximately 6.0. Thus, below a pH of 6, the imidazole ring is mostly [[Protonation|protonated]] (as described by the [[Henderson–Hasselbalch equation]]). The resulting imidazolium ring bears two NH bonds and has a positive charge. The positive charge is equally distributed between both [[nitrogen]]s and can be represented with two equally important [[resonance structure]]s. Sometimes, the symbol '''Hip''' is used for this protonated form instead of the usual His.<ref name=":4" /><ref name=":5">{{Cite web |title=HISTIDINE |url=http://ambermd.org/Questions/HIS.html |access-date=2022-05-12 |website=ambermd.org}}</ref><ref name=":6">{{Cite journal |last1=Dokainish |first1=Hisham M. |last2=Kitao |first2=Akio |date=2016-08-05 |title=Computational Assignment of the Histidine Protonation State in (6-4) Photolyase Enzyme and Its Effect on the Protonation Step |journal=ACS Catalysis |language=en |volume=6 |issue=8 |pages=5500–5507 |doi=10.1021/acscatal.6b01094 |s2cid=88813605 |issn=2155-5435|doi-access=free }}</ref> Above pH 6, one of the two protons is lost. The remaining proton of the imidazole ring can reside on either nitrogen, giving rise to what are known as the N1-H or N3-H [[tautomer]]s. The N3-H tautomer is shown in the figure above. In the N1-H tautomer, the NH is nearer the backbone. These neutral tautomers, also referred to as Nδ and Nε, are sometimes referred to with symbols '''Hid''' and '''Hie''', respectively.<ref name=":4">{{Cite journal |last1=Kim |first1=Meekyum Olivia |last2=Nichols |first2=Sara E. |last3=Wang |first3=Yi |last4=McCammon |first4=J. Andrew |date=March 2013 |title=Effects of histidine protonation and rotameric states on virtual screening of M. tuberculosis RmlC |journal=Journal of Computer-Aided Molecular Design |language=en |volume=27 |issue=3 |pages=235–246 |doi=10.1007/s10822-013-9643-9 |issn=0920-654X |pmc=3639364 |pmid=23579613|bibcode=2013JCAMD..27..235K }}</ref><ref name=":5" /><ref name=":6" /> The imidazole/imidazolium ring of histidine is [[aromatic]] at all pH values.<ref>{{cite journal |doi=10.1016/S0022-2860(03)00282-5 |title=Five-membered heterocycles. Part III. Aromaticity of 1,3-imidazole in 5+n hetero-bicyclic molecules |year=2003 |last1=Mrozek |first1=Agnieszka |last2=Karolak-Wojciechowska |first2=Janina |last3=Kieć-Kononowicz |first3=Katarzyna |journal=Journal of Molecular Structure |volume=655 |issue=3 |pages=397–403 |bibcode=2003JMoSt.655..397M}}</ref>
The acid-base properties of the imidazole side chain are relevant to the [[catalyst|catalytic mechanism]] of many [[enzyme]]s.<ref name=":0">{{Cite journal|last=Ingle|first=Robert A.|title=Histidine Biosynthesis|journal=The Arabidopsis Book|volume=9|pages=e0141|doi=10.1199/tab.0141|pmc=3266711|pmid=22303266|year=2011}}</ref> In [[catalytic triad]]s, the basic nitrogen of histidine abstracts a proton from [[serine]], [[threonine]], or [[cysteine]] to activate it as a [[nucleophile]]. In a histidine [[proton shuttle]], histidine is used to quickly shuttle protons. It can do this by abstracting a proton with its basic nitrogen to make a positively charged intermediate and then use another molecule, a buffer, to extract the proton from its acidic nitrogen. In [[carbonic anhydrase]]s, a histidine proton shuttle is utilized to rapidly shuttle protons away from a [[zinc]]-bound water molecule to quickly regenerate the active form of the enzyme. In helices E and F of [[haemoglobin]], histidine influences binding of dioxygen as well as [[carbon monoxide]]. This interaction enhances the affinity of Fe(II) for O2 but destabilizes the binding of CO, which binds only 200 times stronger in haemoglobin, compared to 20,000 times stronger in free [[haem]]. Under certain conditions, all three ionogenic groups of histidine can be charged thus forminf histidinium cation, then it form double salts.<ref>{{Cite journal |last=Novikov |first=Anton P. |last2=Safonov |first2=Alexey V. |last3=German |first3=Konstantin E. |last4=Grigoriev |first4=Mikhail S. |date=2023-12-01 |title=What kind of interactions we may get moving from zwitter to “dritter” ions: C–O⋯Re(O4) and Re–O⋯Re(O4) anion⋯anion interactions make structural difference between L-histidinium perrhenate and pertechnetate |url=https://pubs.rsc.org/en/content/articlelanding/2024/ce/d3ce01164j |journal=CrystEngComm |language=en |doi=10.1039/D3CE01164J |issn=1466-8033}}</ref>
The tautomerism and acid-base properties of the imidazole side chain has been characterized by <sup>15</sup>N NMR spectroscopy. The two <sup>15</sup>N chemical shifts are similar (about 200 ppm, relative to [[nitric acid]] on the sigma scale, on which increased shielding corresponds to increased [[chemical shift]]). [[NMR]] spectral measurements shows that the chemical shift of N1-H drops slightly, whereas the chemical shift of N3-H drops considerably (about 190 vs. 145 ppm). This change indicates that the N1-H tautomer is preferred, possibly due to hydrogen bonding to the neighboring [[ammonium]]. The shielding at N3 is substantially reduced due to the second-order [[Paramagnetism|paramagnetic]] effect, which involves a symmetry-allowed interaction between the nitrogen lone pair and the excited π* states of the [[aromatic ring]]. At pH > 9, the chemical shifts of N1 and N3 are approximately 185 and 170 ppm.<ref>{{cite book|title=ABCs of FT-NMR|last=Roberts|first=John D.|publisher=University Science Books|year=2000|isbn=978-1-891389-18-4|location=Sausalito, CA|pages=258–9}}</ref>
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