Histidine tautomer

There is also a conformational ambiguity characteristic of the histidine side chain as it is built into electron density maps The two possible orientations about the Cfi-Cy bond are indistinguishable, so the crystal-lographer must select one of these orientations based on chemical intuition [e.g., the availability of hydrogen bond interaction(s) in one particular orientation and not the other]. Additionally, the proper histidine tautomer is likewise selected by chemical intuition. Reynolds et al. (1973) demonstrated that the Ne-H tautomer is the predominant form of free histidine in solution, and these investigators showed that the ratio Ne-H tautomer/N8-H tautomer is approximately 80% 20% (Fig. 13). 

The target is also usually considered to have a single titration state and to be unaffected by the position of the probe. However, the GRID program does allow for probe-induced switching between histidine tautomers. 

AMI semiempirical calculations have shown that, as far as tautomerism is concerned, there is a structural relationship between jS-dicarbonyl compounds and NH-pyrazoles, and in a wide variety of NH-pyrazoles studied " the most stable tautomer was found to be that having the largest single-bond character between the C(3)—C(4) bond. The problem of proton transfer in NH-pyrazole crystals has been subjected to a detailed theoretical study, while a study of the tautomerism of 2-aryl and 2-heteroaryl derivatives of benzimidazole has indicated that tautomerism takes place by the intermolecular relay of protons between stacked molecules. The first report of the stable co-existence of two different histidine tautomers in one peptide crystal structure has appeared. Ab initio calculations have been used to study the tautomerism of both histamine and pyrazolo[3,4-i/]pyridazine in the gas phase and in aqueous solution, and a theoretical study of the NH tautomerism in free-base porphyrin has been undertaken. ... 

The identification of the histidine tautomers in proteins (Scheme 5.48) was established by 2D one-bond correlation spectra (Vc,h 200 Hz) [113]. 

Annular tautomerism of azoles and benzazoles [the nonaromatic tautomers of imidazole 17, 2H and 4(5)H have been calculated at the MP2/6-31G level to be about 15 kcal mol less stable than the IH tautomer (95JOC2865)]. We present here the case of 4(5)-substituted imidazoles, different from the histamine, histidine, and derivatives already discussed. By analogy with these histamines, 4-methylimidazole 17a is often named distal [N(t)H] and 5-methylimidazole 17b, proximal [N(7t)H] (Scheme 9). 

Special attention has been given to the study of tautomeric equilibria in solutions of histidine 22 because the key functional role of such equilibria in proteins is recognized. In aqueous solutions the tautomers of histidine rapidly interconvert and only a single averaged signal is observed for each ring nitrogen (Scheme 10). 

Figure 10-4. The double- and single-site titration models for His and Asp groups [42]. (A) In the double site model, only one X is used for describing the equilibrium between the protonated and deprotonated forms, while the tautomer interversion process is represented by the variable x. (B) In the single-site model, protonation at different sites is represented by different X variables. HSP refers to the doubly protonated form of histidine. HSD and HSE refer to the singly protonated histidine with a proton on the h and e nitrogens, respectively. ASP1 and ASP2 refer to the protonated carboxylic acid with a proton on either of the carboxlate oxygens...

Tanokura M (1983) 1 II-NMstudy R on the tautomerism of the imidazole ring of histidine residues I. Microscopic pK values and molar ratios of tautomers in histidine-containing peptides. Biochim Biophys Acta 742 576-585. 

Classical simulations of MbCO using the CHARMM force field were performed for different tautomerization states of the distal histidine residue (His64) [33], These simulations showed that when His64 is protonated at N,5 (denoted the tautomer) it often rotates such that it exposes either the N,>—H bond or the un-protonated N atom to the CO, as depicted in Scheme 3.4. We... 

Solid samples of histidine, prepared from solutions of different pH, show slow exchange between cationic and neutral forms. Furthermore, only a single tautomer (the NT—H) is observed for the neutral and anionic species. 

Fig. 13. The Ne-H tautomer of histidine is favored for the free amino acid, but within a protein structure either tautomer may be preferentially stabilized due to hydrogen bond arrangements and other environmental factors. For example, the NS-H tautomer is a frequently observed zinc ligand (Chakrabarti, 1990c).

Fig. 18. The carboxylaie-histidine-zinc triad represents indirect carboxylate-zinc interaction across bridging histidine. Both tautomers of histidine are observed, and the hydrogen bond stereochemistry with carboxylate (either aspartate or glutamate) is generally syn. Experimental results and theoretical calculations suggest that the carboxylate-histidine- zinc form may be in equilibrium with the carboxylic acid-histidinate- zinc form, as shown.

For example, if either the histidine or the serine of the triad of subtilisin was replaced by alanine the catalytic activity decreased by a factor of 2 x 106 and replacement of the aspartate of the triad by alanine decreased activity by a factor of 3 x 104.229/258 When Asp 102 of trypsin is replaced by asparagine the catalytic activity falls by four orders of magnitude.259 This may be in part because the histidine in this mutant is hydrogen bonded to Asn 102 as the tautomer with a proton on Ne, the nitrogen that should serve as the catalytic base in step b (Fig. 12-11).260 A mutant in which Ser 214 (see Fig. 12-10) was replaced with alanine is fully active but charged residues in this position interfere with catalysis.261... 

In the solid state, 4(5)-nitro-5(4)-methoxyimidazole exists as a 1 1 mixture of the two prototropic annular tautomers <2004AXB191>. However, in histidine-dipeptides, the tautomer equilibrium (N -H vs. N -H) has been found to vary depending on the nature of the peptide structures <2005JA12544>. 

In the MAS NMR spectra of histidine-dipeptides, the C chemical shifts for and C span a large range (up to 13 ppm) and are highly influenced by the tautomer effect and intermolecular interactions <2005JA12544>. The imidazole ring chemical shifts of 50 (158.6, 123.8 (Vcf = 36.0), 131.0 ppm, Scheme 14) resemble more closely those of l-methyl-5-(/i-tolyl)-4-trifluoromethyl-l//-imidazole (137.6, 128.8 ( cF = 37.4Hz), 133.0ppm). Based on this observation, it was proposed that in the solid state 50 most likely assumes the tautomeric form 50a rather than 50b <2001JHC773>. 

The preparation of the active site depends on the docking tools being used. This step involves the addition of hydrogen atoms avoiding atomic clashes assignment of appropriate protonation states of titrat-able residues and correct tautomers of histidine residues, and involvement of structural water molecules in the binding cavity. 

IUPAC IUB nomenclature recommendations (1983), reproduced in full in Amino Acids, Peptides, and Proteins, 1985, Vol. 16, The Royal Society of Chemistry, p. 387 and in Eur.J.Biochem., 1984,138, 9, encourage the retention of trivial names for the common a-amino acids, but systematic names are relatively straightforward thus, L-alanine is 2S-aminopropanoic add and L-histidine is 2S-amino-3-(imidazol-4-yl)-propanoic add (the name for the predominant tautomer). 

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