Electronic Structure and Physicochemical Properties Characterization of the Amino Acids 12−26 of TP53:  A Theoretical Study

Abstract

PNC-27, a synthetic peptide, is derived from the TP53-HDM2 binding domain that include TP53 amino acids 12-26 linked with 17 amino acids from the antennapedia protein transference domain. This peptide induces membrane rupture in tumor cells through toroidal pores formation and has motivated several experimental studies; nonetheless, its mechanism of biological action remains unknown to date. Herein, we present a theoretical study at the Hartree-Fock and density functional theory (B3LYP) levels of theory of TP53 protein residues 12-26 (PPLSQETFSDLWKLL) in order to characterize its electronic structure and physicochemical properties. Our results for atomic and group charges, fitted to the electrostatic potential (ESP) show important reactive sites (L14, S15, T18, S20, L25, and L26), suggesting that these amino acids are exposed to nucleophilic and electrophilic attacks. Analysis of bond orders, intramolecular interactions and of several global reactivity descriptors, such as ionization potentials, hardness, electrophilicity index, dipole moments, total energies, frontier molecular orbitals (HOMO-LUMO), and electrostatic potential, led us to characterize active sites and the electronic structure and physiochemical features that taken together may be important in understanding the specific selectivity for this peptides type's cancer-cell membrane lysis properties.

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

“…1). Studies carried out in other peptides and biological molecules that possess aminoacyl groups have shown that a smaller DE value is evidence of a more acidic group [7,10,21,22]. In Table I, we have reported values for the deprotonation energies for the CNS tripeptide and their derivatives at the B3LYP/6-311þG(2d,2p)// B3LYP/6-311þG(d,p) level of theory, whereas it may be observed that the bond (N1AH2) of the CNS peptide possesses a smaller value for DE with respect to their derivatives that possess electron donor groups, and larger values when compared with the peptides possessing electron withdrawing substituent groups [see Figs.…”

“…Besides, if hydrogen-bond donors or acceptors are arranged in particular geometries, hydrogenbonding interactions become very specific, with additive and often cooperative strengths. Thus, hydrogen bonding between functional groups occurring in biological molecules plays an important role in the electronic density of these bonds, as well as in their physicochemical and structural features [4][5][6][7]. In this work, we are interested in analyzing the effect that causes the electron donor and electron withdrawing substituent's groups in the side chain of the asparagine amino acid on the electronic, physicochemical, structural properties, and stability of derivatives of Cys-As-Ser (CNS) peptide with anti-inflammatory activity.…”

Studies of regioselectivity of large molecular systems using DFT based reactivity descriptors

“…In a very recent study, Barrientos-Salcedo et al, 329 successfully reproduced experimental findings of reactivity segment as well as the reactive atomic sites of TP53 using DFT based reactivity descriptors. Therein, PNC-27 peptide derived amino acid sequence PPLSQETFSDLWKLL (aa 12-26) 330 was analyzed in three fragments: PPLSQ, ETFS, and DLWKLL (with carboxyl terminal ends in all cases).…”

“…5. They revealed 329 that PPLSQ, ETFS, and DLWKLL fragments studied, have important electrophilic sites such as Q16 (C71), D21 (C12), E17 (C17), P13 (C19), L26 (C103), S15 (C52), S20 (C53), L14 (C33), T18 (C18) and L25 (C82), suggesting that these amino acids are exposed to nucleophilic attacks on these atoms. Also, from the negative charge on nitrogen atoms such as Q16 (N76 and N59), K24 (N80), E17 (N1), D21 (N1), S20 (N42), and W23 (N23) and oxygen atoms S20 (O57), T18 (O24), S15 (O56), D21 (O15 and O16), and Q16 (O75), and reinforce the proposal that the segment (17-20, ETFS) is essential for the biological effect.…”

“…2 ), 20 electrophilicity index (w)(eqn ( 34)), 157 and the spatial extent measured though the hR 2 i, Barrientos-Salcedo et al observed 329 that the ETFS fragment exhibits a larger value for ionization potential, which might be related with the greater global chemical stability of these fragments, i.e., larger ionization potential values may indicate smaller oxidative effects, and they observed that PPLSQ and DLWKLL show a decreasing potential order. Moreover from the hydrogen atom charges, they concluded that these atoms might be forming hydrogen bonds (i.e., intramolecular interactions), which might contribute in increasing the stability of these (i.e., PPLSQ and DLWKLL) peptides structures.…”