Histidine, calculations

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). 

DET calculations on the hyperfine coupling constants of ethyl imidazole as a model for histidine support experimental results that the preferred histidine radical is formed by OH addition at the C5 position [00JPC(A)9144]. The reaction mechanism of compound I formation in heme peroxidases has been investigated at the B3-LYP level [99JA10178]. The reaction starts with a proton transfer from the peroxide to the distal histidine and a subsequent proton back donation from the histidine to the second oxygen of the peroxide (Scheme 8). 

FIGURE 5.7. A FEP surface for PT between serine and histidine in trypsin (the calculations are taken from Ref. 4). 

A. A Simplified EVB Calculation of a Proton Transfer between Cysteine and Histidine in Water. (The reaction is represented in an oversimplified way by assigning all the histidine residual charges to a single nitrogen)... 

FIGURE 8.8. Calculated free-energy profile for the reaction of carbonic anhydrase. g2(a) and g2(b) designate the states where the proton acceptors are water and histidine respectively. 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

Another advantage of PB based pKa calculations is that effects of electrolytes are readily accounted for in the PB equation. The Coulombic contribution in conjunction with salt dependence to the abnormally depressed pAVs of histidine in staphylococcal nuclease has been experimentally tested [56], Recently, the methodology used in the PB calculations (Eqs. 10-11 and 10-12) has been combined with the generalized Born (GB) implicit solvent model [94] to offer pKa predictions at a reduced computational cost [52],... 

Equations (12.36) and (12.40) are the basis of the LRA method for calculating pi a shifts [59]. Indeed, to obtain the pKa shift due to the protein environment, we perform the same calculation for the protein and for a small molecule in solution, analogous to the side chain of interest. For a histidine side chain, for example, one would choose imidazole or methylimidazole in solution as a model compound. The pKa shift due to the protein environment will then have the form ... 

Figure 3.4 shows the models used in the calculations of the active center. They are of the type FeP-AB (FeP = iron-porphyrin, AB = CO, NO, 02), Heme-AB (AB = CO, NO, 02), and FeP(Im)-AB (Im=imidazole). The axial imidazole ligand mimics the effect of the proximal histidine amino acid (Fig. 3.2). 

The magnetic parameters of aquo-Mb obtained from Fig. 44 are collected in Table 15.1. The theoretical A values for the heme and histidine nitrogen, which are about 50% smaller than the observed values, have been determined by Mun et al.242), using an extended Hiickel-type calculation. According to these authors, the agreement between theoretical and experimental values could perhaps be improved further by considering electron core polarization effects. 

In the late 1950s it was shown that imidazole catalyzes the hydrolyses of />-nitrophenyl acetate (7, 76) and that histidine was at the active site of a-chymotrypsin (2). These findings led Katchalski ei al. (39) to synthesize a number of histidine-containing polymers for evaluation as catalysts. Second-order rate constants were calculated on the basis of the concentration of neutral imidazole, that is, k2 = (A bs — .)/a[IM], where k , is the rate constant in the absence of catalyst and a is the fraction ionized. Some of these rate constants appear in Table I. All of the polymers possess less than... 

Although histidine may not be needed beyond infancy, histidine has been reconunended for children and adults based on a calculation of the histidine... 

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