It is well known that only twenty of amino acid are used for the synthesis of protein. The reason for this restriction is still unknown, but such choice is obviously caused by the physical-chemical properties of these molecules [1]. Electronic properties of amino acid side chains, such as inductive and field effects still have not been investigated in details. Quantum-chemical calculations of the influence of R-groups can help to evaluate their role in amino acid pairing. Dwyer [2] and Grantham [3] indicated fundamental role of substituent effects of amino acid side chains in the protein structure. Dwyer attempted, to estimate quantitatively these effects using quantum mechanics calculations [2]. Kolaskar et al. selected 6 'obligatory' amino acids (Ser, Val, Leu, Asp, Gly and Pro) based on the comparative analysis of the conformational similarity of amino acid residues [4]. Amino acid residues cover a wide range of shapes, sizes in many atomic and molecular interactions. The residues determine the broad variety of bio-physicochemical properties that are fundamental in ascertaining macromolecular structures and functional activities. Based on their electronic properties a classification of amino acid type was described - known as Taylor classification [5]. Amino acid residues are classified into three groups, depending on their polarity: polar (Arg, Lys, His, Gln, Asn, Asp and Glu), weak polar (Ala, Pro, Gly, Thr and Ser) and nonpolar (Cys, Val, Met, Ile, Leu, Phe, Tyr and Trp) [6]. Naturally occurring amino acids can be grouped based on their similarity of physical-chemical properties. A collection of physical-chemical properties of amino acids will be helpful to study macroscopic properties of proteins (such as aggregation), perform sequence comparison or understand conservation of functionally important residues in a protein family (physico-chemical signatures). Venkatarajan et al. collated 242 properties for the 20 naturally occurring amino acids and created a database named APDbase (Amino acid Physico-chemical properties Database) [7]. The huge majority of researches of electronic properties of amino acid side chains relate to conformation preference, little or nothing is known about their role in peptide synthesis. From our point of view, this process is not less important. This article is our modest attempt to shed light on this issue (Figure 1).

Figure 1: Amino acids: R = H (Gly), CH₃ (Ala), CH₂OH (Ser), CH₂COOH (Asp), (CH₂)₃NHC=NHNH₂ (Arg), CH(CH₃)₂ (Val), CHOHCH₃ (Thr), (CH₂)₂COOH (Glu), CH₂CH(CH₃)₂ (Leu), CH₂SH (Cys),CH₂C₃H₃N₂ (His), (CH)₄NH₂ (Lys), CHCH₃CH₂CH₃ (Ile), CH₂C₆H₄OH (Tyr), CH₂C=ONH₂ (Asn), (CH₂)₂SCH₃ (Met), (CH₂)C₈H₆N (Trp), CH₂C₆H₅ (Phe), (CH₂)₂C=ONH₂(Gln), C₄H₈N (Pro).

The density functional theory (DFT) is a quantum computational method used in physics, chemistry and biology for investigation of the electronic structure of atoms and molecules [8]. The properties of a many-electron system can be determined by using functionals, which in this case is the spatially dependent electron density. Hence the name of density functional theory comes from the use of functionals of electron density. DFT is among the most popular and versatile methods available in computational biology. Unlike the wavefunction, which is not a physical reality, electron density is a physical characteristic of molecules. Hybrid methods, as the name suggests, attempt to incorporate some of the more useful features from ab initio methods (specifically Hartree-Fock methods) with some of the improvements of DFT mathematics. Hybrid methods, such as B3LYP [9-11] most commonly used for computational chemistry and Biology. Calculations were performed using software,”Priroda-8” in regime of the reaction coordinate [12].

It is known that the electronic structure of the amino acids is one of the main factors, which promote or hinders the formation of a peptide bond. Concerning with this, the values of charges on the carbon atom of the carbonyl group - q(C₃ ), on the oxygen atom of the hydroxyl group q(O₂) and on the nitrogen atom of the amine group q(N₆), and also the orders of the CO and NH bonds (Pco, P_NH) and the dipole moments (μ) were calculated using DFT. The results of the calculations are given in Table 1. The search for a quantitative correlation between the calculated physicochemical characteristics of amino acids and their percentage content in proteins (%) (Table 1) is not always successful. However, in some cases the qualitative dependence is observed. In particular, comparative analysis shows a symbate correlation between percentage of content (%) and the dipole moment.

Table 1: Electronic (qi - charges on atoms, Pij-bond orders, -dipole moments, content of amino acids in proteins (%)
R = H (Gly), CH₃ (Ala), CH₂OH (Ser), CH₂COOH (Asp), (CH₂)₃NHC=NHNH₂ (Arg), CH(CH₃)₂ (Val), CHOHCH₃ (Thr), (CH₂)₂COOH (Glu), CH₂CH(CH₃)₂ (Leu), CH₂SH (Cys), CH₂C₃H₃N₂ (His), (CH)₄NH₂ (Lys), CHCH₃CH₂CH₃ (Ile), CH₂C₆H₄OH (Tyr), CH₂C=ONH₂ (Asn), (CH₂)₂SCH₃ (Met), (CH₂)C₈H₆N (Trp), CH₂C₆H₅ (Phe), (CH₂)₂C=ONH₂(Gln).

From the Tables 2 and 3 is clear that the values of the content of amino acids (%) and their dipole moments (μ) are grouped in three ranges: high, average and low. Consequently, depending on the calculated values of the amino acid dipole moments (μ), their percentage in proteins (%) can be estimated.

Table 2: The values of the percentage content in proteins and dipole moments of proteinogenic amino acids.

Table 3: The values of the percentage content in proteins and dipole moments of proteinogenic amino acids.

Table 4 shows the values of the charges on the carbon atoms of the carbonyl group - q (C3), the nitrogen of the amino group - q (N6) and oxygen - the q (-O-) hydroxyl group, and also the order of the C-O bond – PCO. Using the numerical values of these characteristics, a number of amino acids were constructed in the direction of their decrease in content:

Table 4: Charges on C₃, N₆, -O- atoms and bond order P_CO of proteogenic amino acids.

q(C₃): Arg > Thr, Asn, Lys > Ala, Glu, Gln, Met, Thr; (a)

q(N₆): Arg > Thr, Asn > Lys > Ala, Glu, Gly; (b)

q(-O-): Pro> Lys > Thr > Arg > His > Trp > Val > Asp > Gln > Phe > Gly, Glu > Leu, Ala, Asn; (c)

P(C-O): Cys > Gly > Thr > Leu > His > Ala, Trp > Met, Ile, Phe, Tyr, Pro, Val, Asn, Asp > Arg, Glu, Gln, Lys. (d)

The increase in the positive charge C₃ of the carbon atom of the carbonyl group promotes the nucleophilic attack of aminoacyladenyl acid on the carboxy group to form an ester and the subsequent break of the C-O bond. As can be seen from the series (a), arginine has the highest nucleophilic property of the C₃ atom, and threonine has the lowest one. A similar distribution is observed for the nitrogen atom-N₆ (row b). The charge of hydroxyl oxygen (-O-) is given in the row (c). The highest values are observed for proline and lysine (-0.163 and -0.160), and the lowest values for asparagine (-0.089). Consequently, asparagine must have a high acidity, since the hydroxyl oxygen atom weakly retains the acid proton due to the low value of the electronic charge. The row (d) shows that Lysine has the lowest value (1.07) of the order of the C-O (Pco) bond, and Cysteine has the highest one (1.17). Consequently, Lysine promotes the breakdown of the C-O bond and therefore easily forms the peptide bond, but cysteine - has the difficulties for the C-O bond breakage.

Based of tabular data of dipole moments, it is possible to construct a series of amino acid polarities:

Gly

For the thirteen proteinogenic amino acids: alanine, arginine, asparagine, glutamine, glutamic acid, histidine, leucin, lysine, phenylalanine, proline, threonine, tyrosine and valine, are observed the antibatic dependence of their percentage [13] content from the dipole moment. The remaining amino acids (red triangles on the chart) are eliminated from the observed correlation, which may be caused by additional steric effects (Figure 2).

Figure 2: Percentage of amino acids appearance in proteins on its dipole moment.

Electronic characteristics of proteogenic amino acids: charges on carbonyl carbon atom qC₃, amine nitrogen atom qN₆ and hydroxyl oxygen atom qO₂, as well as the orders of CO and NH bonds P_CO and P_NH and dipole moments μ are calculated using techniques of DFT. The qualitative correlation between the polarity (dipole moment) and the percentage content of amino acids in proteins was found. Using the numerical values of these characteristics, the row of the amino acids was built in the direction of their decrease. Among them, we can single out (a) and (b) series that are similar in composition and structure, which can be explained by the main contribution of C₃ and N₆ charges in the formation of the peptide bond [14,15].

This work supported by the Shota Rustaveli National Science foundation Grant No: 217732.

The authors declare that they have no conflict of interest.

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent was obtained from all individual participants included in the study.