Acidity of the Amino Acids

3 Acidity of the Amino Acids The critical role that amino acids play in biochemistry demands special attention from physical organic chemists. Of particular interest is the acidity of these compounds. Perhaps surprising is that a systematic examination of the gas phase acidities of most of the amino acids was not reported until 1992. Poutsma and Kass combined experimental and computational studies of all 20 common naturally occurring amino acids. The 

The agreement between the experimental and computational deprotonation enthalpies is quite good. The correlation coefficient of a plot of the two sets of values is 0.9799, but all the computed values lie within the error bars of each experiment. While an ordered list by DPE of the 20 amino acids are not quite the same using the experimental and computed values, there are really very small disagreements. 

Embedded within this list of DPE of the amino acids are two unexpected results concerning what is the most acidic proton. The first case is cysteine, where one might ask which is more acidic, the carboxylate proton or the thiol proton Kass and Poutsma note that, in general, the gas-phase acidity of carboxylic acids is greater than thiols the DPE of propanoic acid (CH3CH2CO2H) is 347.7 kcal mol at G3B3 (347.2 expt about 6 kcal mol less than that of ethanethiol (CH2CH2SH  

0 at G3B3 and 354.2 expt They optimized the structure of cysteine and its conjugate base at B3LYP/aug-cc-pVDZ. We will discuss cysteine conformers 

Another unconventional deprotonation is seen with tyrosine. Gas-phase experiments by Kass indicate that deprotonation of tyrosine leads to a 70 30 mixture of the phenoxide 16 to carboxylate 17 anions. Kass optimized the structures of tyrosine and its two possible conjugate bases 16 and 17 at B3LYP/aug-cc-pVDZ, and computed the two DPEs at G3B3.17 is predicted to be 0.2 kcal mol lower in energy than 16 at B3LYP and slightly more stable at G3B3 (0.5 kcal mol ). However, both computational methods fail to predict the DPEs of acetic acid and phenol 

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There are several examples of metabolites where the tetramic acid domain is teasingly disguised. In these cases, it is difficult to be definitive about the nature of the apparent modification unless this is substantiated by biosynthetic studies. The case of lactacystin (5), Fig. (2), has already been considered. Another example is presented by the oxazolomycin group of antibiotics, e.g. (Ill), found in strains of Streptomyces [179]. Biosynthetic studies indicate that the carboxylic acid of the amino acid required to form tetramic acids contributes to the formation of the 3-lactone [180]. In this section, metabolites that probably have a tetramic acid origin are presented. 

Delocalization of the positive charge causes the nitrogen on arginine to be the most basic, and hence its carboxylic group the least acidic of the amino acids in the table. 

The disulfide group has little effect on the acidity of the amino acid, therefore cystine is approximately neutral. 

The acidities of the amino acids may be distinguished by using a weak organic base (in this case, 2,4,6-collidine). A- strong acid will be strongly held by the base and will hence move at a relatively slow rate on the paper chromatogram. The weakest acid will move fastest on the paper chromatogram. 

Hence arginine is the most basic (least acidic) of the amino acids being considered. The least easily pro-tonated amino acid is glutamic acid. This is due to the electron withdrawing effect of the carboxylic acid group O 1... 

In fact,that the compound is the most acidic of the amino acids considered is clearly evident from the presence of a second carboxyl group, which, itself, has acidic properties, Thus glutamic acid, being the only dicarboxylic amino acid, is the most acidic one. 

Protein respiration almost certainly involves first a hydrolytic breakdown by proteinases and peptidases to give free amino acids. Of the amino acids of plant cells, only glutamic acid is known to be actively oxidised by an enzyme universally distributed, the glutamic acid dehydrogenase ... 

X-alanine, 2-aminopropanoic acid, C3H7NO2, CH3.CH(NH2)C00H. M.p. 297X. One of the amino-acids obtained by the hydrolysis of proteins. 

C3H7NO3, CH20H-CHNH2-C02H. Colourless crystals m.p. 228 C (decomp.). It is one of the amino-acids present in small quantities among the hydrolysis products of proteins. 

Abstract. A smooth empirical potential is constructed for use in off-lattice protein folding studies. Our potential is a function of the amino acid labels and of the distances between the Ca atoms of a protein. The potential is a sum of smooth surface potential terms that model solvent interactions and of pair potentials that are functions of a distance, with a smooth cutoff at 12 Angstrom. Techniques include the use of a fully automatic and reliable estimator for smooth densities, of cluster analysis to group together amino acid pairs with similar distance distributions, and of quadratic progrmnming to find appropriate weights with which the various terms enter the total potential. For nine small test proteins, the new potential has local minima within 1.3-4.7A of the PDB geometry, with one exception that has an error of S.SA. 

The class of a pair of amino acids in positions i, A of a sequence s depends on the labels Si and s, of the amino acids and the residue distance i — k, and is specified through a suitably constructed class table, and... 

Figure 7-14. All-atom and united-atom representation of the amino acid isoleucine. In this example, 13 atoms, which are able to form explicit non-bonding interactions, are reduced to only four pseudo-atoms,...

It is important to notice that the united-atom simplification cannot be applied to functional hydrogens which are involved in the formation of a hydrogen hond or a salt bridge. This would destroy interactions important for the structural integrity of the protein. Removing the hydrogen at the u-carbon of the peptide backbone is also dangerous, because it prevents racemization of the amino acid. 

Physical Properties. Glycine is a colourless crystalline solid soluble in water. Owing to the almost equal opposing effects of the amino and the carboxylic groups. its aqueous solution is almost neutral (actually, slightly acidic to phenolphthalein) and glycine is therefore known as a neutral ampholyte. f It exhibits both acidic and basic properties. 

These salts are by far the most readily prepared derivatives (having sharp m.ps.) of the amino-aromatic sulphonic acids. 

Benzoates. Dissolve 0-5 g. of the amino acid in 10 ml. of 10 per cent, sodium bicarbonate solution and add 1 g. of benzoyl chloride. Shake the mixture vigorously in a stoppered test-tube remove the stopper from time to time since carbon dioxide is evolved. When the odour of benzoyl chloride has disappeared, acidify with dilute hydrochloric acid to Congo red and filter. Extract the solid with a little cold ether to remove any benzoic acid which may be present. RecrystaUise the benzoyl derivative which remains from hot water or from dilute alcohol. 

Dissolve 0 01 g. equivalent of the amino acid in 20 ml. of N sodium hydroxide solution and add a solution of 2 g. of p-toluenesulphonyl chloride in 25 ml. of ether shake the mixture mechanically or stir vigorously for 3-4 hours. Separate the ether layer acidify the... 

Dissolve 0 01 g. equivalent of the amino acid in 0 03 g. equivalent of N sodium hydroxide solution and cool to 5° in a bath of ice. Add, with rapid stirring, 0 -01 g. equivalent of 2 4-dichlorophenoxyacetyl chloride dissolved in 5 ml. of dry benzene at such a rate (5-10 minutes) that the temperature of the mixture does not rise above 15° if the reaction mixture gels after the addition of the acid chloride, add water to thin it. Remove the ice bath and stir for 2-3 hours. Extract the resulting mixture with ether, and acidify the aqueous solution to Congo red with dilute hydrochloric acid. Collect the precipitate by filtration and recrystallise it from dilute alcohol. 

Place 0-5 g. of the amino acid and 1 0 g. of phthalic anhdride in a Pyrex test-tube and immerse the lower part of the tube in an oil bath, which has previously been heated to 180-185°. Stir the mixture occasionally during the first 10 minutes and push down the phthalic anhydride which sublimes on the walls into the reaction mixture with a glass rod. Leave the mixture undisturbed for 5 minutes. After 15 minutes, remove the test-tube from the bath when the liquid mass solidifies, invert the test-tube and scrape out the excess of phthalic anhydride on the walls. RecrystaUise the residue from 10 per cent ethanol or from water. 

Similar ligand-ligand interactions have been reported for a large number of ternary -amino acid complexes, built up of two different amino acid.s. A compilation of 72 examples is presented in reference 39. The extra stabilisation due to ligand-ligand interactions in these complexes depends on the character of the amino-acid side chains and amounts to 0.34 - 0.57 kJ/mole for combinations of aromatic and aliphatic side chains and 0.11 - 6.3 kJ/mole when arene - arene interactions are possible. ... 

NMR signals of the amino acid ligand that are induced by the ring current of the diamine ligand" ". From the temperature dependence of the stability constants of a number of ternary palladium complexes involving dipeptides and aromatic amines, the arene - arene interaction enthalpies and entropies have been determined" ". It turned out that the interaction is generally enthalpy-driven and counteracted by entropy. Yamauchi et al. hold a charge transfer interaction responsible for this effect. 

An alternative drivirg force could involve a donor - acceptor interaction. The electron-poor pyridine ring that is coordinated to the copper cation can act as electron acceptor with respect to the aromatic ring of the -amino acid. The fact that donating substituents on the amino acid increase the efficiency... 

The reactivity of the amino radical has not yet been investigated. Alkaline hypochlorite oxidation, known in the pyridine series to yield azo derivatives (155,156). and photolysis of N,N-dichloro derivatives, which may be obtained by action of sodium hypochlorite on amino derivatives in acidic medium (157). should provide interesting insight on this reactivitv. 

However, prior protective acetylation of the amino group leads to a good yield of the 5-nitro compound [2-acetamido-4-methyl-5-nitroselenazole, m.p. 185 C (19)j. Similarly. 2-diethylamino-4-methy)-selenazole with nitric acid gives the. 5-nitro derivative [vellow needles, m.p. 93°C (26)],... 

The condensation of thioacetic acid with amino acids under drastic conditions provides a useful new synthesis of thiazoles (Scheme 146) (668, 669). Instead of the amino acid, Af-acyl <279) or N-thioacylamino acids (278) are used. 

Hydrolysis of the following compound in concentrated hydrochlonc acid for several hours at 100°C gives one of the amino acids in Table 27 1 Which one" Is it optically active" ... 

Ecample Miller and Rich investigated the conformational consequences of substitutions on an amino acid in cyclosporin A, an important immunosuppressive drug. One of the amino acids in this cyclic undecapeptide is (2, 3r, 4r, 6e)-3-Hydroxy-4-methyl-2-(methylamino)-6-octenoic acid (MeBmt). It is essential for biological activity. 

Weber, P. L. Buck, D. R. Capillary Electrophoresis A Past and Simple Method for the Determination of the Amino Acid Composition of Proteins, /. Chem. Educ. 1994, 71, 609-612. This experiment describes a method for determining the amino acid composition of cyctochrome c and lysozyme. The proteins are hydrolyzed in acid, and an internal standard of a-aminoadipic acid is added. Derivatization with naphthalene-2,3-dicarboxaldehyde gives derivatives that absorb at 420 nm. Separation is by MEKC using a buffer solution of 50 mM SDS in 20 mM sodium borate. 

Fig. 3. (a) Chemical stmcture of a synthetic cycHc peptide composed of an alternating sequence of D- and L-amino acids. The side chains of the amino acids have been chosen such that the peripheral functional groups of the dat rings are hydrophobic and allow insertion into Hpid bilayers, (b) Proposed stmcture of a self-assembled transmembrane pore comprised of hydrogen bonded cycHc peptides. The channel is stabilized by hydrogen bonds between the peptide backbones of the individual molecules. These synthetic pores have been demonstrated to form ion channels in Hpid bilayers (71). 

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