Metal complex–DNA binding: Insights from molecular dynamics and DFT/MM calculations

Spinello, Angelo; Terenzi, Alessio; Barone, Giampaolo

doi:10.1016/j.jinorgbio.2013.03.010

Cited by 30 publications

(33 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…48,49 By considering the single nucleotides in the 33-nucleotides long fragment, the varying codon involves positions 16, 17, and 18. The topology file of the PTC124 molecule was generated using ACPYPE.…”

Section: Methodsmentioning

confidence: 99%

Toward a Rationale for the PTC124 (Ataluren) Promoted Readthrough of Premature Stop Codons: A Computational Approach and GFP-Reporter Cell-Based Assay

et al. 2014

Self Cite

View full text Add to dashboard Cite

The presence in the mRNA of premature stop codons (PTCs) results in protein truncation responsible for several inherited (genetic) diseases. A well-known example of these diseases is cystic fibrosis (CF), where approximately 10% (worldwide) of patients have nonsense mutations in the CF transmembrane regulator (CFTR) gene. PTC124 (3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)-benzoic acid), also known as Ataluren, is a small molecule that has been suggested to allow PTC readthrough even though its target has yet to be identified. In the lack of a general consensus about its mechanism of action, we experimentally tested the ability of PTC124 to promote the readthrough of premature termination codons by using a new reporter. The reporter vector was based on a plasmid harboring the H2B histone coding sequence fused in frame with the green fluorescent protein (GFP) cDNA, and a TGA stop codon was introduced in the H2B-GFP gene by site-directed mutagenesis. Additionally, an unprecedented computational study on the putative supramolecular interaction between PTC124 and an 11-codon (33-nucleotides) sequence corresponding to a CFTR mRNA fragment containing a central UGA nonsense mutation showed a specific interaction between PTC124 and the UGA codon. Altogether, the H2B-GFP-opal based assay and the molecular dynamics (MD) simulation support the hypothesis that PTC124 is able to promote the specific readthrough of internal TGA premature stop codons.

show abstract

Section: Methodsmentioning

confidence: 99%

Toward a Rationale for the PTC124 (Ataluren) Promoted Readthrough of Premature Stop Codons: A Computational Approach and GFP-Reporter Cell-Based Assay

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…The resulting insight is also relevant, among other things, for modeling and rationalizing the interaction of drugs with DNA, following any type of covalent[9] and/or noncovalent drug–DNA binding with particular emphasis on DNA intercalators. [10]…”

Section: Introductionmentioning

confidence: 99%

B‐DNA Structure and Stability as Function of Nucleic Acid Composition: Dispersion‐Corrected DFT Study of Dinucleoside Monophosphate Single and Double Strands

Barone

Guerra²,

Bickelhaupt

2013

ChemistryOpen

Self Cite

View full text Add to dashboard Cite

We have computationally investigated the structure and stability of all 16 combinations of two out of the four natural DNA bases A, T, G and C in a di-2′-deoxyribonucleoside-monophosphate model DNA strand as well as in 10 double-strand model complexes thereof, using dispersion-corrected density functional theory (DFT-D). Optimized geometries with B-DNA conformation were obtained through the inclusion of implicit water solvent and, in the DNA models, of sodium counterions, to neutralize the negative charge of the phosphate groups. The results obtained allowed us to compare the relative stability of isomeric single and double strands. Moreover, the energy of the Watson–Crick pairing of complementary single strands to form double-helical structures was calculated. The latter furnished the following increasing stability trend of the double-helix formation energy: d(TpA)2

show abstract

“…Since no experimental intercalated structures are available for ZnL 2 + , we obtained two possible pockets of the intercalated system in alternating AT and GC dodecanucleotides from MD simulations by following a recently reported procedure. [26] The root mean square deviation (RMSD) for all non-hydrogen atoms is shown in Figure S8 of the Supporting Information, which shows that the initial structure of both intercalation complexes suddenly changes after about 1 ns, by about 3 in the RMSD. Then, oscillations of about 2 of RMSD occur around the equilibrium geometry, largely involving the tails of the two dodecanucleotides and much less the structure of the metal complex and the four stacked DNA bases of the intercalation pocket.…”

Section: Dna Intercalationmentioning

confidence: 99%

A Theoretical and Experimental Investigation of the Spectroscopic Properties of a DNA‐Intercalator Salphen‐Type Zn^II Complex

Biancardi¹,

Burgalassi²,

Terenzi³

et al. 2014

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

The photophysical and DNA-binding properties of the cationic zinc(II) complex of 5-triethylammonium methyl salicylidene ortho-phenylenediiminato (ZnL(2+)) were investigated by a combination of experimental and theoretical methods. DFT calculations were performed on both the ground and the first excited states of ZnL(2+) and on its possible mono- and dioxidation products, both in vacuo and in selected solvents mimicked by the polarizable continuum model. Comparison of the calculated absorption and fluorescence transitions with the corresponding experimental data led to the conclusion that visible light induces a two-electron photooxidation process located on the phenylenediiminato ligand. Kinetic measurements, performed by monitoring absorbance changes over time in several solvents, are in agreement with a slow unimolecular photooxidation process, which is faster in water and slower in less polar solvents. Moreover, structural details of ZnL-DNA binding were obtained by DFT calculations on the intercalation complexes between ZnL and the d(ApT)2 and d(GpC)2 dinucleoside monophosphate duplexes. Two main complementary binding interactions are proposed: 1) intercalation of the central phenyl ring of the ligand between the stacked DNA base pairs; 2) external electrostatic attraction between the negatively charged phosphate groups and the two cationic triethylammonium groups of the Schiff-base ligand. Such suggestions are supported by fluorescence titrations performed on the ZnL/DNA system at different ionic strengths and temperatures. In particular, the values of the DNA-binding constants obtained at different temperatures provided the enthalpic and entropic contributions to the binding and confirmed that two competitive mechanisms, namely, intercalation and external interaction, are involved. The two mechanisms are coexistent at room temperature under physiological conditions.

show abstract

Metal complex–DNA binding: Insights from molecular dynamics and DFT/MM calculations

Cited by 30 publications

References 81 publications

Toward a Rationale for the PTC124 (Ataluren) Promoted Readthrough of Premature Stop Codons: A Computational Approach and GFP-Reporter Cell-Based Assay

Toward a Rationale for the PTC124 (Ataluren) Promoted Readthrough of Premature Stop Codons: A Computational Approach and GFP-Reporter Cell-Based Assay

B‐DNA Structure and Stability as Function of Nucleic Acid Composition: Dispersion‐Corrected DFT Study of Dinucleoside Monophosphate Single and Double Strands

A Theoretical and Experimental Investigation of the Spectroscopic Properties of a DNA‐Intercalator Salphen‐Type Zn^II Complex

Contact Info

Product

Resources

About

Metal complex–DNA binding: Insights from molecular dynamics and DFT/MM calculations

Cited by 30 publications

References 81 publications

Toward a Rationale for the PTC124 (Ataluren) Promoted Readthrough of Premature Stop Codons: A Computational Approach and GFP-Reporter Cell-Based Assay

Toward a Rationale for the PTC124 (Ataluren) Promoted Readthrough of Premature Stop Codons: A Computational Approach and GFP-Reporter Cell-Based Assay

B‐DNA Structure and Stability as Function of Nucleic Acid Composition: Dispersion‐Corrected DFT Study of Dinucleoside Monophosphate Single and Double Strands

A Theoretical and Experimental Investigation of the Spectroscopic Properties of a DNA‐Intercalator Salphen‐Type ZnII Complex

Contact Info

Product

Resources

About

A Theoretical and Experimental Investigation of the Spectroscopic Properties of a DNA‐Intercalator Salphen‐Type Zn^II Complex