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

Biochemical recognition processes mediated through π-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 π-stacking interaction of the nucleobase/tryptophan pair. From the optimized structures of these species, evaluation of the donor−acceptor HOMO−LUMO gap (Δε_d→a) suggests that this parameter is a promising predictor of π-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.