Amino-acids and Peptides

1 Amino Acids Exist in a Three-Dimensional World 

Why is it important to specify the three-dimensional structure of amino acids  

Sign in at www.thomsonedu.com/login to test yourself on these concepts. 

A protein supplement available in a health food store. The label lists the amino acid content and points out the essential amino acids. 

The synthesis. X-ray structure, and electronic spectra of trnfi5-[Co(en)2Ci(Boc-L-val)]BF4 (Boc = t-butyloxycarbonyl) has been described/ The complex was prepared by reaction of tran5-[Co(en)2(OH)Cl] and an active ester form of Boc-L-valine. Cobalt(III) is coordinated in a distorted octahedral fashion by four N atoms, a Cl atom, and a carboxylate oxygen from the Boc-L-valine ligand. The 

The rate of intramolecular amide hydrolysis in cobalt(III) complexes has been studied as models for zinc(II)-containing peptidases such as carboxypeptidase A, thermolysin, and angiotensin-converting enzyme. The cobalt(IIl) complexes (8) and (9) were prepared by hydrogen peroxide oxidation of the corresponding 

Amino-acids and Peptides.— The co-monoprotonated forms of lysine and ornithine are reactive in the formation of complexes with nickel(ii) and cobalt(ii). 

Displacement of triclycine (G3) from [CuH-aGg]- by macrocyclic tetra-amine ligands (Table 2), is much slower than the corresponding process with trien. The proposed mechanism involves initial binding at the carboxyl site followed by proton transfer to the adjacent peptide link, thus weakening the copper(ii)-peptide bond. The rate with [CuH 2G3] is 4 x 10 higher than the rate with [Cu(edta)] , which has no proton acceptor site and requires nucleophilic displacement by the macrocycle. 

Dissociation of triglycine from palladium(n) proceeds by an initial rapid breaking of the carboxyl-palladium bond followed by sequential protonation and cleavage of the metal-peptide linkages at rates of 23.4 and 2.7 s at 25 °C. 

Tervalent copper and nickel are involved in the autoxidation reactions of [Cu(H 3G4)] and [Ni(H 3G4)] respectively. In the case of nickel, decomposition of [Ni(H 3G4)] proceeds by decarboxylation of the terminal carboxy-group adjacent to the peptide nitrogen. - With copper, decomposition of [Cu-(H sG4)] proceeds through a carbon-centred free radical produced by abstraction of a hydrogen atom from the peptide backbone. Bulky carbon substituents assist the stabilization of the higher-oxidation state ions, and a study of the stabilities of leucyl tripeptide complexes with copper(ii) and nickel(u) has been reported. Copper(iii) and nickel(iii) tripeptide complexes of a-aminoisobutyric acid are thermally stable but are readily decomposed by photochemical pathways. Resonance Raman and other studies with copper(iii) peptide complexes have also been reported.  

Amino acids, peptides, and proteins are important nutritions in foods and agricultural products. Amino acids and peptides in foods and agricultural products have been determined by CE coupled with a carbon and a copper detection electrodes. 

In 2003, Wang et al. determined tryptophan, tyrosine, tyramine, and tryptamine in rice spirit by MECC-AD [9]. The detection electrode was a carbon disk electrode that worked at a detection potential of 0.8 V (vs. SCE). The four analytes were well separated within 14 min in a piece of a 70-cm-long fiised-silica capillary at a separation voltage of 20 kV in a 20 mM borate buffer (pH 10.4) containing 30 mM SDS. 

In 2002, Jin et al. investigated the precapillary derivatization of 20 amino acids with naphthalene-2,3-dicarboxaldehyde (NDA) and CN [10]. All these derivatized amino acids could be oxidized on the carbon liber microdisk bundle electrode except proline at a detection potential of 1.15 V (vs. SCE). CZE with ECD was employed for the analysis of 19 amino acids (including arginine, lysine, ornithine tryptophan, histidine isoleucine, leucine phenylalanine, methionine, glutamine, tyrosine, valine, threonine, serine, alanine, glycine. 

Besides a carbon electrode, a copper electrode has also been employed in the direct detection of amino acids and peptides in combination of CZE. In 1994, Baldwin et al. developed a method based on a copper disk electrode for the direct detection of amino acids and peptides after they were separated by CZE [12]. The separation medium was 50 or 100 mM 

NaOH aqueous solution. The use of copper electrodes permitted the direct detection of amino acid species in CE at constant applied potentials and without derivatization. The detection limits they obtained varied from 1 to 10 fmol for most amino acids. The feasibility and the application of the approaches they developed have been demonstrated included the determination of amino acids in human urine, of the dipeptide aspartame in diet soft drinks, and of pentapeptide products of a solid-phase synthesis procedure. 

Synthesis of macrocyclic peptides and depsipeptides with cytotoxic activity 88YZ1115. 

Oligopeptides are more reactive than the a-amino acids, which do not carry any additional electrophilic factional groups. It has been pointed out in Section I that the enhanced reactivity of oligopeptides may be attributed to the activation of the carbonylic group, which is even further enhanced when the amino-group is protonated. 

When you see this icon, sign in at this book s premium website at www.cengage.com/login to access videos, Pre-Lab Exercises, and other oniine resources. 

Because amino acids have both a basic (the amine) and an acidic (the carboxylic acid) functional group, the state of protonation of the molecule varies with pH as shown in Equation 24.1. The presence of a functional group in the side chain may have considerable influence upon the position of this equilibrium at different pHs. The pH at which the vast majority of the molecules are in the zwitterionic form, and therefore have a net charge of zero, is referred to as the isoelectric point, pi. An amino acid is least soluble in water at its isoelectric point, which is different for each amino acid. If the side chain bears an ionizable group such as a carboxylic acid or an amine, the state of protonation of that functional group will also vary as a function of pH. However, the amino acids used in the exjjeriments in this chapter are nonpolar, so we will not concern ourselves with the complexities associated with ionizable side chains. 

An amide bond formed between the nitrogen atom of one amino acid and the acyl carbon atom of another is referred to as a peptide bond, a term coined in 1902 by the Nobel laureate Emil Fischer (see the Historical Highlight at the end of Chapter 23 for an account of the life of this famous chemist). For example, aspartame (2), the active ingredient in the artificial sweetener NutraSweet , is the methyl ester of a dipeptide derived from joining a molecule of L-aspartic acid (Asp) and 

The synthesis of peptides and proteins in nature is a complex process that you may study in detail in a biochemistry course. However, because short peptides and their derivatives may exhibit useful properties and potent biological activities, chemists in academic and pharmaceutical laboratories have develop ed efficient methods for their synthesis. 

The fundamental problem in the synthesis of peptides is that amino acids must be connected in a defined sequence by specifically forming a peptide bond between the carboxylic acid group of one amino acid and the amino group of another. The potential difficulties arising in such endeavors may be illustrated by considering the synthesis of the simple dipeptide Ala-Phe from the individual amino acids L-alanine (Ala) (3) and L-phenylalanine (Phe) (4), as seen in Equation 24.2. Formation of peptide bonds in a random manner could lead to four different dipeptides. This mixture arises because the carboxylic acid of Ala may react with either the amino 

Among the basic amino acids, SERS of histidine has been studied on a roughened Cu electrode [255] in water and D2O solutions. Depending on the pH of the solution histidine exists in five different ionic forms Eq. (6.7), which can be distinguished by the shift in Raman/SERS peak positions as studied by Martusevicius et al. [255]  

SERS substrates [257]. The di pep tide data were used as the basis set for predicting 

Mushrooms are a source of simple chlorinated amino acids (7), and several new examples are known. Thus, Amanita vergineoides has furnished (2S,4Z)-2-amino-5-chloro-4-pentenoic acid (915) (964), and a full account of the isolation of (2S)-2- 

Cyanobacteria blooms can pose an extremely serious threat to human health (970-972), and some of the causative toxins contain halogen. The fresh water toxic cyanobacterium Oscillatoria agardhii produces oscillaginin A (916), which features the novel 3-amino-10-chloro-2-hydroxydecanoic acid, and is the source of the micro-cystins, which are heptatoxins (973). The prolific cyanobacterium Lyngbya majuscula from Curacao has furnished the novel barbamide (917) (974) and dechlorobarbamide (918) (975). Extensive biosynthetic studies show that the amino acids leucine, cysteine, and phenylalanine are involved in barbamide production (976-982). The chlorination of leucine is of great interest and may involve a radical mechanism (976, 980-983). 

Reef provided 920-922, and the absolute configuration of the latter metabolite was established as shown (985). Dysidea fragilis from the South China Sea has yielded dysamide D (923) (986), and Dysidea chlorea from Micronesia afforded 12 new polychlorinated diketopiperazines, dysamides I-T (924—935) (987). In addition, this study (987) confirmed the structure of dysamide E (936) (988). Based on previous assignments the absolute configurations of 924—936 are believed to be those indicated. A Pacific Ocean collection of Dysidea sp. provided dysamide U (937), which is the first trichlorinated member of the diketopiperazine family to be identified (989). 

The simple herbacic acid (938) was isolated from Dysidea herbacea from the Great Barrier Reef, and may be a precursor to more complex trichloromethyl metabolites (990). Another collection of Dysidea sp. from Australia s Great Barrier Reef yielded five new metabolites (939-943) for which the absolute stereochemistry was determined by correlation with (-)-(.S )-4,4,4-trich loro-3-methyl butanoic acid (991). Dysidea herbacea from the Great Barrier Reef contains (-)-neodyside-nin (944), which is an isomer of the well-known and often isolated dysidenin. 

This new metabolite belongs to the L-series of trichloroleucine peptides and is a rare example of a non-/V-methylated trichloroleucine amino acid (992). Another sample of this sponge from the same locale has yielded the new thiazoles 945 and 946, which are also related to dysidenin (993). The Panamanian Lyngbya majuscula has afforded the new dysidenamide (947), pseudodysidenin (948), and nordysidenin (949), which is the first report of dysidenin-like compounds from a free-living cyanobacterium (994). 

Due to their zwitterionic character, the amino acids are difficult to convert quantitatively and uniformly into suitable GC derivatives. Numerous methods have now been reported toward meeting this difficult goal. From the 19 amino acids contained commonly in protein hydrolyzates, the trifunctional compounds are particularly difficult to handle in a quantitative fashion. The problems here result from a different reactivity of various fimctional groups as well as only a limited solubility of certain amino acids in the reaction media. 

Arginine and histidine are particularly notable for their derivatization problems [475-477]. Sometimes, even when proper derivatives can eventually be made, they can be easily hydrolyzed or catalytically degraded in an insufficiently inert GC system. 

Numerous volatile derivatives that have been reported in the literature over the years shall not be comprehensively reviewed in this chapter. The general approaches toward derivatization of various functional groups from the organic-chemical point of view have already been discussed. As much of the previous work in this area has already been reviewed by Husek and Macek [478], MacKenzie [479] and Jaeger et al. [480], only the key points and new directions will be emphasized here. 

It is most desirable that a given amino acid should form a single-derivative peak after treatment with a single derivatization agent. Unfortunately, that is not the case for many important determinations. Thus, for example, permethylation [481] and the formation of W-dimethylaminomethylene alkyl esters [482] appeared limited to only some amino acids. Persilylation of all amino acid functional groups with potent silyl donors [483] comes perhaps closest to definition of a universal reaction , but even here some problems are encountered (a) derivatization can be time-consuming (b) multiple derivatives are occasionally formed even under precautions (c) Si-N bonds are moisture-sensitive and (d) truly quantitative derivatization is difficult to achieve for all protein amino acids. 

A useful alternative to esterification procedure appears to be the formation of oxazolidinone derivatives using 1,3-dichlorotetrafluoroacetone, as reported recently by Husek and co-workers [246,247] the resulting heterocyclic nitrogen is further acylated with heptafluorobutyric anhydride. This procedure, which is applicable to 20 common amino acids, was found to be both rapid and sensitive [247]. 

Chapter 7. Purification of Biochemicals — Amino Acids and Peptides 

This section includes amino acid derivatives and related compounds. 

A/-Acetyl-L-alaninamide [15962-47-7] M 130.2, m 162 . Ciystallise the amide repeatedly from EtOH/diethyl ether. The ( )-isomer crystallises from HjO and has m 157-158 . [Greenstein Winitz The Chemistry of the Amino Acids J. Wiley, Vol 3 p 1838 1961. de Jong Rec Trav Chim Pays Bas 19 288 1900, Fischer Otto Chem Ber 36 2106 1903, Beilstein 4 H 295.] 

W-Acetyl-L-alanyl-L-alanyl-L-alaninamide [29428-34-0] M 272.3, m 295-300 . Crystallise the tripeptide derivative from MeOH/diethyl ether. 

Acetyl-a-amino- -butyric acid [34271-24-4] M 145.2, pK 3.72. Crystallise the acid twice from water 

Dehydrogenation of nitrogen-containing compounds 10.1.1. Amino acids and peptides 

In an attempted synthesis of phenylglycinatocobalt(III) complexes, a 2-iminocarboxylato derivative, [ Co(HN=CH(C H )C00 (tetraamine) 

In this scheme, the p-peroxodicobalt(III) derivative is first formed, then intramolecular oxidative dehydrogenation of a coordinated dipeptide occurs. The corresponding intermediate has been detected by polarography. Displacement of the oxidized ligand by excess free dipeptide leads to a cobalt(III) complex, which does not react with O.  

Therefore, the above reaction is irreversible and not part of a catalytic cycle. 

Peptide oxidation with 0-insertion is treated in Section 10.2.4. 

The detailed structural study of metalloproteins was preceded by the study of small molecule metal complexes of amino adds and peptides [478]. The development of force fields for modeling metalloproteins might, logically, also begin with molecular mechanics modeling of amino acid and peptide complexes that have metal-ligand interactions of the type seen in the metalloprotein of interest. In this way, force-field 

Cyclic peptides can be viewed as a step on the way from the modeling of unconstrained peptides to folded proteins. The copper(II) complexes of cyclic octapeptides have been investigated by molecular mechanics and EPR spectroscopy (M M -E P R), and the structures were found to be in accord with those of closely related complexes (see also Chapter 10) [262,483]. More recently, the MM-EPR method has been extended by DFT [410], and used to characterize the mono- and dicopper(II) complexes of the smaller cyclic peptide Westiallamide and some analogues [484]. Similar combined approaches are also applicable to metalloproteins. 

One motivation behind the modeling of metalloproteins has been the need to visualize the structures of proteins that caimot be crystallized. In order to do this 

Another approach to representing the metal center in a molecular-mechanics-based model has been developed for zinc(II) centers and apphed to the modeling of the interaction of natural substrates and inhibitors of the enzyme human carbonic anhydrase [157, 492, 493]. Stmcturally characterized four-, five- and six-coordinate small-molecule complexes of zinc(II) were analyzed to determine the distribution of bond lengths and angles about the zinc ion. A function was developed that was able to reproduce these structural features, and was added to the program YETI [494], developed for modeling smaU-molecule-metalloprotein interactions. 

The solution structures of a number of metalloproteins with paramagnetic metal centers were determined with molecular mechanics and dynamics in combination with NMR spectroscopy (see also Chapter 10) [417-420]. Due to the complexity of the molecules, for metalloproteins a crystal structure of the compound or a derivative is often needed for the definition of the starting geometry. Molecular dynamics is then used to find low-energy conformers. The dynamics calculations also allow the visualization of areas of large flexibility, and this can lead to some understanding of the enzyme mechanism. 

The physiologically most important components of hving beings are proteins, the carriers of basic physiological and biochemical functions. Their molecules are extraordinarily complex and varied but in spite of this complexity their structures are built from only 20 relatively simple molecules - the amino adds. Before investigating these biologically important amino acids which are the products of hydrolysis of proteins, we shall describe the structure and properties of this class of compounds in general. 

The molecules of amino acids have two functional groups with different properties, the basic amino group and the acidic carboxyl group. Because the amino group can be bound to different carbon atoms on the hydrocarbon chain, the names of these compounds are derived from the position of this functional group. However, for this class of compounds, the traditional nomenclature in which the C-atoms are labeled not by numbers, but by letters of the Greek alphabet is still in use. In addition, the letter a does not correspond to the carbon atom labeled with number 1, but to the atom with the number 2. In this nomenclature there are a, p, y amino acids, etc. 

All 20 amino acids obtained from natural proteins belong to the a-amino acids and can be represented by the general formula H2NCHRCOOH. They differ only in the substituent R. 

Amino acids are amphoteric compounds the carboxylic groups given them acidic properties and the amino groups give them a basic character. Their amphoteric behavior is shown in the next scheme. 

Amino acids are well soluble in water, because they can appear in the form of a dipolar ion called, by the German word, Zwitterion. This ion can be considered as the product of self-protonation the amino group is protonated by the proton that comes from the carboxyl group. 

05 M phosphate buffer has about three times the ionic strength of the 0.05 M Tris buffer at pH 7.5. 

The common amino acids are simply weak polyprotic acids. Calculations of pH, buffer preparation, and capacity, and so on, are done exacdy as shown in the preceding sections. Neutral amino acids (e.g., glycine, alanine, threonine) are treated as diprotic acids (Table l-l). Acidic amino acids (e.g., aspanic. acid, glutamic acid) and basic amino acids (e.g., lysine, histidine, arginine) are treated as triprotic acids, exactly as shown earlier for phosphoric acid. 

Calculate the pH of a O.l M solution of (a) glycine hydrochloride, (b) isoelectric glycine, and (c) sodium glycinate. 

Start halfway lo 1st equiv, point) First Equivalence Point pKni (fial/iuaj to 2nd equiv. point) Second Equivalence Point 

Because of the proximity of the amino and carboxyl groups, ihe carboxyl group is a stronger acid than that of acetic acid. The y in the denominator cannot be ignored. 

Aspartic acid R = CHjCOOH Giutamic acid R = CH,CH,COOH 

AVK (one letter). The ends of a peptide are labelled as the amino end or amino terminus, and the earboxy end or carboxy terminus. 

Large peptides of biologieal signifieanee are known by their trivial names e.g., insulin is an important peptide eomposed of 51 amino aeid residues. 

All living organisms can synthesize amino acids. However, many higher animals are deficient in their ability to synthesize all of the amino acids they need for their proteins. Thus, these higher animals require certain amino 

The carbon skeletons of the amino acids can be used to produce metabolic energy. Several amino acids can be classified as glucogenic and ketogenic because of their degradation products. 

Reagents i, PhaP CHCN, DMAP ii, O3, MeOH, CHaCIa  

---

Modern methods of amino-acid and peptide analysis, have enabled the complete amino-acid sequence of a number of proteins to be worked out. The grosser structure can be determined by X-ray diffraction procedures. Proteins have molecular weights ranging from about 6 000 000 to 5 000 (although the dividing line between a protein and a peptide is ill defined). Edible proteins can be produced from petroleum and nutrients under fermentation. 

This chapter revolves around proteins The first half describes the building blocks of proteins progressing through amino acids and peptides The second half deals with pro terns themselves... 

Derivatives such as 3-fluoro-4-nitropyridine [13505-01 -6] (396) or the 1-oxide [769-54-0] (397) have been used to characteri2e amino acids and peptides. 5-Eluoro-3-pyridinemethanol [22620-32-2] has been patented as an antihpolytic agent (398). A promising antidepressant, l-(3-fluoro-2-pyridyl)pipera2ine hydrochloride [85386-84-1] is based on 2-chloro-3-fluoropyridine [17282-04-1] (399). 

Specialist Periodical Reports Amino-Acids, Peptides, and Proteins, Royal Society of Chemistry, London,. Vols. 1-16 (1969-1983) Amino Acids and Peptides, Vols. 17-21 (1984-1990). 

The procedure described is essentially that of Shioiri and Yamada. Diphenyl phosphorazidate is a useful and versatile reagent in organic synthesis. It has been used for racemlzatlon-free peptide syntheses, thiol ester synthesis, a modified Curtius reaction, an esterification of a-substituted carboxylic acld, formation of diketoplperazines, alkyl azide synthesis, phosphorylation of alcohols and amines,and polymerization of amino acids and peptides. - Furthermore, diphenyl phosphorazidate acts as a nitrene source and as a 1,3-dipole.An example in the ring contraction of cyclic ketones to form cycloalkanecarboxylic acids is presented in the next procedure, this volume. 

It is known that not all reactions proceed in the same manner on all adsorbent layers because the material in the layer may promote or retard the reaction. Thus, Ganshirt [209] was able to show that caffeine and codeine phosphate could be detected on aluminium oxide by chlorination and treatment with benzidine, but that there was no reaction with the same reagent on silica gel. Again the detection of amino acids and peptides by ninhydrin is more sensitive on pure cellulose than it is on layers containing fluorescence indicators [210]. The NBP reagent (. v.) cannot be employed on Nano-Sil-Ci8-100-UV2S4 plates because the whole of the plate background becomes colored. 

Differences in the materials employed for the layers can also become evident when chemical reactions are performed on them. Thus, Macherey-Nagel report that the detection of amino acids and peptides by reaction with ninhydrin is less sensitive on layers containing luminescent or phosphorescent indicators compared to adsorbents which do not contain any indicator [7]. 

The detection limits for amino acids and peptides are between 50 and 200 pmol per chromatogram zone [9], 400 pg for 5-hydroxyindolylacetic acid [11] and 300 pg for dihydroxyergotoxin [19]. 

The p-nitrophenol fonned as a byproduct in this reaction is easily removed by extraction with dilute aqueous base. Unlike free amino acids and peptides, protected peptides are not zwitterionic and are more soluble in organic solvents than in water. 

The last comprehensive review of the chemistry of oxazolones covered the literature through 1954. Most of the studies up to that time stemmed from either interest in the role of azlactones as precursors of a-amino acids and peptides or the monumental studies on penicillin, which, for a time, was thought to possess an oxazolone ring, rather than the correct jS-lactam moiety. 

Thomson MOW Click Organic Interactive to learn to estimate isoelectric points for simple amino acids and peptides. 

Cohn, E. J., and Edsall, J. T., Proteins, Amino Acids, and Peptides as Ions and Dipolar Ions, ... 

Stereoselectivity and reactivity in complexes of amino-acids and peptides. R. D. Gillard, Inorg. Chim. Acta, Rev., 1967,1,69-86 (102). 

Table 25 Compounds T8[(CH2)3NR)R2]8 obtained from the reaction of T8[(CH2)3NH3Cl]8 with Z-protected amino acids and peptides...

A. Interactions of [organotinllV)]" with amino acids and peptides 365... 

Nagy covered a large number of publications on the amino acids and peptides and on the other complexes discussed. 

The most widely studied interactions between biologically active ligands and organotin(lV) cations relate to the amino acids and their derivatives (N- or S-protected amino acids and peptides), though new data on several of the most commonly occurring amino acids are still being published. This is specially true for aqueous speciation studies. Nice and very detailed reviews were published in this area by Molloy and Nath. ... 

Applications of the oxalate-hydrogen peroxide chemiluminescence-based and fluorescence-based assays with NDA/CN derivatives to the analysis of amino acids and peptides are included. The sensitivity of the chemiluminescence and fluorescence methods is compared for several analytes. In general, peroxyoxalate chemiluminescence-based methods are 10 to 100 times more sensitive than their fluorescence-based counterparts. The chief limitation of chemiluminescence is that chemical excitation of the fluorophore apparently depends on its structure and oxidation potential. 

Michaeli, A. Feitelson, J. (1994). Reactivity of singlet oxygen toward amino acids and peptides. Photochemistry and Photobiology, Vol.59, No.3, (March 1994), pp. 284-289, ISSN 0031-8655. 

Park, E. Y. Murakami, H. Matsumura, Y. (2005). Effects of the addition of amino acids and peptides on lipid oxidation in a powdery model system. Journal of Agricultural and Food Chemistry, Vol. 53, No. 21, (September 2005), pp. 8334-8341 7, ISSN 0021-8561. 

Greenstein, J. P., Studies on multivalent amino acids and peptides, J. Biol. Chem., 118, 321-329, 1937. 

Selective protection and activation of amino acids and peptides has now reached a highly sophisticated level and requires specialised knowledge for the most efficient use. 

A new chapter on amino acids and peptides, which emphasizes the manner in which the properties of biologic peptides derive from the individual amino acids of which they are comprised. 

The importance of lipophilicity to bitterness has been well established, both directly and indirectly. The importance of partitioning effects in bitterness perception has been stressed by Rubin and coworkers, and Gardner demonstrated that the threshold concentration of bitter amino acids and peptides correlates very well with molecular connectivity (which is generally regarded as a steric parameter, but is correlated with the octanol-water partition coefficient ). Studies on the surface pressure in monolayers of lipids from bovine, circumvallate papillae also indicated that there is a very good correlation between the concentration of a bitter compound that is necessary in order to give an increase in the surface pressure with the taste threshold in humans. These results and the observations of others suggested that the ability of bitter compounds to penetrate cell membranes is an important factor in bitterness perception. 

Gardner reported that excellent, quantitative relationships also exist between the thresholds of amino acids and peptides and the connectivity indices ( a )- These relationships are of the same order of significance as the relationship between thresholds and hydrophobicity, but they are applicable to a wider range of compounds. 

---