Effects of Nucleobase Metalation on Frontier Molecular Orbitals: Potential Implications for π-Stacking Interactions with Tryptophan

Abstract

Biochemical recognition processes mediated through pi-stacking interactions are a potential target for rational drug synthesis. A combination of electrostatic, hydrophobic, solvation, charge-transfer, induction, and dispersion interactions has been used to account for the three-dimensional arrangements observed in such motifs. A principal example involves the interaction of purine and pyrimidine rings of nucleic acids with aromatic amino-acid residues such as tryptophan, phenylalanine, and tyrosine. Protonation, alkylation, or coordination of a metal ion such as Pd(II) or Pt(II) to a nucleobase strengthens this interaction by lowering the energy of the lowest unoccupied molecular orbital (LUMO) of the modified nucleobase and improving overlap with the highest occupied molecular orbital (HOMO) in N-acetyl tryptophan. The relative energy difference between the frontier orbitals of isolated molecules, obtained using Density Functional Theory (DFT), is explored as a predictive tool for the strength of the pi-stacking interaction of the nucleobase/tryptophan pair. From the optimized structures of these species, evaluation of the donor-acceptor HOMO-LUMO gap (Deltaepsilon d-->a) suggests that this parameter is a promising predictor of pi-stacking strength for the donor-acceptor pairs presented in this study. The analysis correlates well with experimental association constants, measured by fluorescence spectroscopy, of metallated and alkylated nucleobases with tryptophan in comparison to free nucleobases.

Enhancement of the physicochemical properties of [Pt(dien)(nucleobase)]2+ for HIVNCp7 targeting

“…30–33 We have previously used the relative energy difference between the frontier orbitals of isolated molecules as a predictive tool for the strength of the π-stacking interaction of the nucleobase/tryptophan pair. 13 The analysis correlated well with experimental association constants, measured by fluorescence spectroscopy, of metallated (Pt, Pd) and methylated nucleobases with tryptophan in comparison to free nucleobases. 13 …”

“…13 The analysis correlated well with experimental association constants, measured by fluorescence spectroscopy, of metallated (Pt, Pd) and methylated nucleobases with tryptophan in comparison to free nucleobases. 13 …”

“…9–11 Nucleobase metallation, analogous to protonation or alkylation, enhances their π–π stacking to aromatic amino acids. 12,13 Metallation of 9-EtGua in [M(dien)(9-EtGua)] n + (M = Pt, Pd n = 2; M = Au, n = 3) produces a 2–5-fold increase in the association constant with N -acetyltryptophan ( N -AcTrp) compared to the free nucleobase. 12–15 The general enhancement also extends to pyrimidines such as 1-mecytosine and even heterocyclic aromatic ligands based on pyridine and thiazole.…”

Zinc finger proteins as templates for metal ion exchange: Substitution effects on the C-finger of HIV nucleocapsid NCp7 using M(chelate) species (M = Pt, Pd, Au)

“…In this respect we have consistently drawn an analogy between alkylation and platination (metalation) in these reactions [5,9,10,35]. On this basis, the Cys 49 is also highly likely to be the initial site of attachment of a metal ion.…”

Synthesis, experimental and theoretical characterization of Cu(II) complex of 2-chloropyrimidine

“…Pyrimidines with high physiological importance as the components of nucleic acids are very attractive compounds (Anzellotti et al, 2008;Jacobson et al, 2002). They provide the sites that have bonding potential to the metallic ions.…”