Binding mechanism of anti-cancer chemotherapeutic drug mitoxantrone to DNA characterized by magnetic tweezers

Kreft, Dennis; Wang, Ying; Rattay, Michael; Tœnsing, Katja; Anselmetti, Dario

doi:10.1186/s12951-018-0381-y

Cited by 35 publications

(18 citation statements)

References 55 publications

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“…Molecular PSs formed by fused-ring aromatic moieties are known to non-covalently bind to DNA strands as intercalators between neighboring base pairs, where the PS/DNA complex is stabilized by stacking interactions between the aromatic rings of the drug and the nucleobases [ 24 , 25 ]. This is the case of anthraquinone derivatives, whose DNA intercalative binding have been extensively investigated [ 36 , 38 , 54 , 55 ]. Despite the presence of strong staking interactions, both the PS and the nucleobases can undergo large molecular motions, inducing important conformational changes in the system.…”

Section: Resultsmentioning

confidence: 99%

Stacking Effects on Anthraquinone/DNA Charge-Transfer Electronically Excited States

Cárdenas

Nogueira

2020

Molecules

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The design of more efficient photosensitizers is a matter of great importance in the field of cancer treatment by means of photodynamic therapy. One of the main processes involved in the activation of apoptosis in cancer cells is the oxidative stress on DNA once a photosensitizer is excited by light. As a consequence, it is very relevant to investigate in detail the binding modes of the chromophore with DNA, and the nature of the electronically excited states that participate in the induction of DNA damage, for example, charge-transfer states. In this work, we investigate the electronic structure of the anthraquinone photosensitizer intercalated into a double-stranded poly(dG-dC) decamer model of DNA. First, the different geometric configurations are analyzed by means of classical molecular dynamics simulations. Then, the excited states for the most relevant poses of anthraquinone inside the binding pocket are computed by an electrostatic-embedding quantum mechanics/molecular mechanics approach, where anthraquinone and one of the nearby guanine residues are described quantum mechanically to take into account intermolecular charge-transfer states. The excited states are characterized as monomer, exciton, excimer, and charge-transfer states based on the analysis of the transition density matrix, and each of these contributions to the total density of states and absorption spectrum is discussed in terms of the stacking interactions. These results are relevant as they represent the footing for future studies on the reactivity of anthraquinone derivatives with DNA and give insights on possible geometrical configurations that potentially favor the oxidative stress of DNA.

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Section: Resultsmentioning

confidence: 99%

Stacking Effects on Anthraquinone/DNA Charge-Transfer Electronically Excited States

Cárdenas

Nogueira

2020

Molecules

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“…The experiment success ratio is verified by digital holographic centrifugal force microscopy (DH-CFM), an improved version of CFM proposed by Halvorsen and Wong (2010a). After performing 200 experiments, the results indicated that the experimental success ratio obtained by the proposed method was approximately ten times higher than that obtained by the method widely used in H-SMFS, such as magnetic tweezers (Kreft et al 2018;Kriegel et al 2017Kriegel et al , 2018Lipfert et al 2010) and CFM (Hoang et al 2016;Yang et al 2016b).…”

Section: Introductionmentioning

confidence: 86%

“…The common method here is cited from the methods often used in magnetic tweezers (Kreft et al 2018;Kriegel et al 2017Kriegel et al , 2018Lipfert et al 2010) and is also mentioned in the CFM system (Hoang et al 2016;Yang et al 2016b). The result following this common method has been shown in Fig.…”

Section: Efficiency Analysismentioning

confidence: 99%

Sample preparation method to improve the efficiency of high-throughput single-molecule force spectroscopy

Jin

Zeng

et al. 2019

Biophys Rep

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Inefficient sample preparation methods hinder the performance of high-throughput single-molecule force spectroscopy (H-SMFS) for viscous damping among reactants and unstable linkage. Here, we demonstrated a sample preparation method for H-SMFS systems to achieve a higher ratio of effective target molecules per sample cell by gas-phase silanization and reactant hydrophobization. Digital holographic centrifugal force microscopy (DH-CFM) was used to verify its performance. The experimental result indicated that the DNA stretching success ratio was improved from 0.89% to 13.5%. This enhanced efficiency preparation method has potential application for force-based DNA stretching experiments and other modifying procedures.

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“…Molecular PSs formed by fused-ring aromatic moieties are known to non-covalently bind to DNA strands as intercalators between neighboring base pairs, where the PS/DNA complex is stabilized by stacking interactions between the aromatic rings of the drug and the nucleobases [17,18]. This is the case of anthraquinone derivatives, whose DNA intercalative binding have been extensively investigated [29,31,47,48]. Despite the presence of strong staking interactions, both the PS and the nucleobases can undergo large molecular motions, inducing important conformational changes in the system.…”

Section: Sampling the Stacking Binding Pocketmentioning

confidence: 99%

Stacking Effects on Anthraquinone/DNA Charge-Transfer Electronically Excited States

Cárdenas

Nogueira

2020

Preprint

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The design of more efficient photosensitizers is a matter of great importance in the field of cancer treatment by means of photodynamic therapy. One of the main processes involved in the activation of apoptosis in cancer cells is the oxidative stress on DNA once a photosensitizer is excited by light. As a consequence, it is a matter of great relevance to investigate in detail the binding modes of the chromophore with DNA, and the nature of the electronically excited states that participate in the induction of DNA damage, for example, charge-transfer states. In this work, we investigate the electronic structure of the anthraquinone photosensitizer intercalated into a double-stranded poly(dG-dC) decamer model of DNA. First, the different geometric configurations are analyzed by means of classical molecular dynamics simulations. Then, the excited states for the most relevant poses of anthraquinone inside the binding pocket are computed by an electrostatic-embedding quantum mechanics/molecular mechanics approach, where anthraquinone and one of the nearby guanine residues are described quantum mechanically to take into account intermolecular charge-transfer states. The excited states are characterized as monomer, exciton, excimer and charge-transfer states based on the analysis of the transition density matrix, and each of these contributions to the total density of states and absorption spectrum is discussed in terms of the stacking interactions. These results are relevant as they represent the footing for future studies on the reactivity of anthraquinone derivatives with DNA and give insights on possible geometrical configurations that potentially favor the oxidative stress of DNA.

show abstract

Binding mechanism of anti-cancer chemotherapeutic drug mitoxantrone to DNA characterized by magnetic tweezers

Cited by 35 publications

References 55 publications

Stacking Effects on Anthraquinone/DNA Charge-Transfer Electronically Excited States

Stacking Effects on Anthraquinone/DNA Charge-Transfer Electronically Excited States

Sample preparation method to improve the efficiency of high-throughput single-molecule force spectroscopy

Stacking Effects on Anthraquinone/DNA Charge-Transfer Electronically Excited States

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