Binding of berberine to human telomeric quadruplex – spectroscopic, calorimetric and molecular modeling studies

Abstract

This study examines the characteristics of binding of berberine to the human telomeric d[AG3(T2AG3)3] quadruplex. By employing UV‐visible spectroscopy, fluorescence spectroscopy and isothermal titration calorimetry, we found that the binding affinity of berberine to the human telomeric quadruplex is 106. The complete thermodynamic profile for berberine binding to the quadruplex, at 25 °C, shows a small negative enthalpy (ΔH) of −1.7 kcal·mol−1, an entropy change with TΔS of +6.5 kcal·mol−1, and an overall favorable free energy (ΔG) of −8.2 kcal·mol−1 .Through the temperature dependence of ΔH, we obtained a heat capacity (ΔCp) of −94 (± 5) cal·mol−1·K−1. The osmotic stress method revealed that there is an uptake of 13 water molecules in the complex relative to the free reactants. Furthermore, the molecular modeling studies on different quadruplex–berberine complexes show that berberine stacking at the external G‐quartet is mainly aided by the π–π interaction and the stabilization of the high negative charge density of O6 of guanines by the positively charged N7 of berberine. The theoretical heat capacity (ΔCp) values for quadruplex–berberine models are −89 and −156 cal·mol−1·K−1.

Studies on synthesis, characterization, and G-quadruplex binding of Ru(II) complexes containing two dppz ligands

“…This unique activity of telomerase makes the enzyme an ideal probe for tumor diagnosis and a target for cancer chemotherapy [8,9]. Molecules, which have (a) a π-delocalized system, (b) a partial positive charge in the center of the molecular scaffold, and (c) a positively charged substituent to interact with the grooves, loops, and the negatively charged phosphate backbone, most likely interact with and further stabilize G-quadruplexes [10]. Therefore, many research groups have designed and synthesized some molecules with such structures, which are believed to be able to interact with G-quadruplex DNA structures.…”

Determination of in silico rules for predicting small molecule binding behavior to nucleic acids in vitro.

“…The amount of hypochromicity observed here (>38.2%) is consistent with ligands such as TmPyP4 that can interact with the K+ 22mer by both end-stacking and intercalation [132]. However, intercalation of ligands such as TmPyP4 is typically characterized by a bathochromic, red shift of> 15 nm, while reports for ligands that interact by end-stacking such as Berberine are in the range of 8 -12 nm [132,146,203,209,215]. Additionally, it has been reported that intercalation is energetically less favorable than terminal end-stacking due to the challenge of quadruplexes accommodating ligands stacked between existing guanine quartets [209].…”

“…In this class of compounds, the side chains are non-aromatic (Figure 57). Berberine has been shown to bind to predominantly triplex and quadruplex nucleic acids by intercalation or end-stacking [112,[145][146][147]. A preference for AT base pairs is notable for berberine [147].…”

“…These models could provide valuable insights into the possible interaction of Compound 1 with the terminal G-quartets and loop regions that are present in the human telomeric quadruplex structure. The K+ 22mer is polymorphic and is known to adopt several so-called Hybrid structures (Hybrid-l and Hybrid-2) in vitro [146]. are available in silico and were selected for modeling studies as they contain the human telomeric K+ 22mer repeat [196][197]222], but have unique flanking sequences.…”

Computational Methods to Study G-Quadruplex–Ligand Complexes

“…Subsequently, Mulholland and Wu employed the GAFF and parmbsc0 force fields to systematically explore the binding of telomestatin to human telomeric DNA. 99 More recently, combined experimental and computational methods 100 have been used to investigate the interactions between the isoquinoline alkaloid ligands and a 3 + 1 hybrid-type human telomeric quadruplex structure (PDB id 2MB3). 47 In this study, Noureini et al docked the ligands using the ICM-Pro MolSoft molecular modelling suite.…”