The influence of electron donor and electron acceptor groups on the electronic structure of the anti‐inflammatory tripeptide Cys‐Asn‐Ser

Abstract

It has been discussed in the literature that electron delocalization along the peptide backbone and side chain modulates the physical and chemical features of peptides and proteins. The structure and properties of peptides are determined by their charge-density distribution, such that the modification of its side chain plays an important role on its electronic structure and physicochemical properties. Research on Entamoeba histolytica soluble factors led to the identification of the pentapeptide Met-Gln-Cys-Asn-Ser, with anti-inflammatory in vivo and in vitro effects. A synthetic pentapeptide, Met-Pro-Cys-Asn-Ser, maintained the same anti-inflammatory actions in experimental assays. A previous theoretical study allowed proposing the Cys-Asn-Ser tripeptide (CNS tripeptide) as the pharmacophore group of both molecules. This theoretical hypothesis was recently confirmed experimentally. The objective of this work was to study the influence of the electron donor and electron withdrawing substituent groups on the electronic structure and physicochemical properties of the CNS tripeptide derivatives through a theoretical study at the density functional theory level of theory. Our results in deprotonation energies showed that the relative acidity of hydrogen atom (H2) of the serine-amide group increases with the electron withdrawing groups. This result was confirmed by means of a study of bond order. The proton affinities illustrated that the electron donor groups favored the basicity of the amino group of the cysteine amino acid. Atomic charges, Frontier molecular orbitals (HOMO-LUMO), and electrostatic potential isosurface and its geometric parameters permitted to analyze the effect that provoked the electron donor and electron attractor groups on its electronic structure and physicochemical features and to identify some reactive sites that could be associated with the anti-inflammatory activity of tripeptide CNS derivatives.

Importance of asparagine on the conformational stability and chemical reactivity of selected anti-inflammatory peptides

“…We selected the H2 hydrogen atom of the serine amino acid to study the relative acidity of the CNS and CDS [6,29], because this atom is involved in the chemical reactivity and geometric stability of these peptides (see Figs. 1 and 4).…”

“…Thus, small (DE ac ) values imply a more acidic amide (CON1H2) group [6,39,40]. In addition, proton affinity energies ðDE PA Þ provide a good method for analyzing the basicity of the amino group of the cysteine amino acid, in which a larger value is indicative of a more basic molecule.…”

“…In addition, proton affinity energies ðDE PA Þ provide a good method for analyzing the basicity of the amino group of the cysteine amino acid, in which a larger value is indicative of a more basic molecule. Therefore, ðDE PA Þ were calculated utilizing the isodesmic type of reactions, from which good results may be obtained in a relatively inexpensive manner [6,41]. DE PA are given by the following reaction:…”

“…On the other hand, hydrogen bonding interactions becomes very specific when additive effects (often cooperative) occur [23][24][25]; thus, hydrogen bonds between the functional groups of peptides and proteins play a significant role in their physicochemical properties (Acid-Base) and chemical reactivity [8,10,13]. Therefore, quantum chemistry calculations are important to account for substituent effects that may provide insight into these electronic and physicochemical properties [6][7][8][11][12][13][14]26]. According to the latter, in earlier works our investigation group has studied the relationship between the physicochemical and structural properties of a small family of anti-inflammatory peptides [27][28][29].…”

“…Some molecules, such as free radicals and proteins, derive from the invading organism at the site of the damaged tissues, while others are the products of cells participating in the inflammatory response [2][3][4][5]. Several studies have shown that electron delocalization along the amino acid side chains of peptides and proteins could be caused by a substituent group along the peptide backbone; this substitution is significantly important for modifying the behavior of the physicochemical features and the chemical reactivity of peptides and proteins [6][7][8][9][10][11][12]. Also, peptide conformation and protein folding are controlled by several factors, including the following: electronic properties; hydrophobicity; inductive effect; pKa; conformational changes, and steric effects, which in turn might affect the chemical reactivity of molecules with pharmacological activity [7,[13][14][15][16][17][18].…”