A Computational Challenge of Guanine Quadruplex Involvement in Anticancer Antibiotics

Small bioactive molecules show significant propensity to form noncovalent addition complexes with guanine quadruplexes, G4. The stabilization energies of these complexes have been computed precisely at the sufficiently high 6-31G** basis set level of density functional quantum chemical theory, DFT. A decisive factor in present model computations is the adopted size of G4 models, whether these consist simply of stacked quanine quartets, or also involve (deoxy)ribose-phosphate fragments of proper nucleic acids. The challenge is in the preservation of physico-chemical accuracy of DFT computations with increasing sizes of models, involving upwards of 120 atoms for the simplest two-layer G4, plus at least 60 pentose-phosphate linker atoms per each pair of guanine quartets. Bioactive ligand sizes add to the requirements for further rigorous analyses of the roles of G4 complexes in biological processes, which thus remain necessarily open-ended.