Binding of Net-Fla, a Netropsin-Flavin Hybrid Molecule, to DNA: Molecular Mechanics and Dynamics Studies<i>in vacuo</i>and in Water Solution

Ketterlé, Christophe; Gabarro-Arpa, Jacques; Ouali, Mohammed Assam; Bouziane, Mohammed; Auclair, Christian; Helissey, Philippe; Giorgi‐Renault, Sylviane; M, Le Bret

doi:10.1080/07391102.1996.10508911

Cited by 17 publications

(10 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The residence times of water molecules bound closely to proton acceptor or proton donor sites in the cavity are similar to those observed for gapG in the minor groove spine of hydration. The absolute values are consistent with our, and some previous, studies using experimental methods for the determination of the residence times of water molecules [41,50], but are shorter than those of other experimental studies [42].…”

Section: Discussionsupporting

confidence: 92%

Solution structures of a duplex containing an adenine opposite a gap (absence of one nucleotide)

Roll

Ketterlé

Fazakerley

et al. 1999

European Journal of Biochemistry

View full text Add to dashboard Cite

We investigated the behaviour of a 15mer DNA duplex, [5 H d(CAGAGTCACTGGCTC)3 H ].[5 H d(GAGCCAG)3 H + 5 H d(GACTCTG)3 H ] which contained an adenine opposite the gap. Analysis of the NMR data showed the existence of one major species, which was in equilibrium with two minor species. Their relative concentrations varied as a function of pH with a pK a of <4.5. For the major species, the duplex was globally in B conformation with the central adenine stacked in the helix. The two G´C base pairs adjacent to the central adenine were well formed and a gap was present in front of this adenine. For the minor species, major structural perturbations occurred in the centre of the duplex. At neutral pH, the central adenine was involved in a G´A mismatch with G23 adjacent to the gap. Cytosine C7 was then extrahelical and no gap was observed. Under these conditions, the major neutral species corresponded to 70% of the total and the minor species to 30%. At acidic pH, the central adenine of the minor species was protonated and was involved in a G(syn)´A + (anti) mismatch. The difference is that C9 is now extrahelical and G22 is implicated in the mispair. Three-dimensional models were built to initiate molecular dynamic simulations, which were in good agreement with the NMR data. Their structural stability in terms of hydrogen bonding and their flexibility are discussed and the biological significance for the interaction with DNA polymerase is evoked.Keywords: DNA; gap; molecular dynamics; NMR; repair.DNA duplexes containing gaps of one nucleotide may occur as a result of damaging processes, but also as an intermediate during a DNA repair mechanism. The damage product is the result of an oxidative attack on DNA, which has two main origins: normal aerobic cellular metabolism and ionizing radiation [1]. Oxidative damage to DNA is a frequent event: it occurs up to 150 000 times per day per cell (105 times per min per cell; [2]). In aerobic metabolism and after ionizing radiation, the hydroxyl radical is the most important species to reacts with and modify the DNA structure [3,4]. The nature of the damage product depends on the reaction site of the hydroxyl radical on the DNA [5,6]. Hydroxyl attack on the sugars at the C1 H atom leads to base release (abasic sites); attack at the C4 H atom or on the phosphate backbone may lead to single-strand breaks (nicks) or loss of a single nucleotide (gap). Finally, hydroxyl attack on the bases leads to base damage or, ultimately, base release. In these different cases, O-H, phosphate groups or modified sugars are adjacent to the gap The proteins or protein±DNA complexes involved in this mechanism have been the subject of several recent structural or biochemical reports [16±18]. These reports showed that a particular structure of the DNA duplex during the complexation with DNA polymerase b is required for nucleotide insertion. The base facing the gap must be stacked over its neighbouring base in the 5 H direction. This position of DNA in the active site of DNA polymerase is necessary for plac...

show abstract

Section: Discussionsupporting

confidence: 92%

Solution structures of a duplex containing an adenine opposite a gap (absence of one nucleotide)

Roll

Ketterlé

Fazakerley

et al. 1999

European Journal of Biochemistry

View full text Add to dashboard Cite

show abstract

“…Moreover, the diffusion curves of these water molecules reveal a third class of water molecules with diffusion fingerprints close to those belonging to the minor groove spine of hydration. The best trapped water molecules in the cavity of gapG have residence times in the range 100-300 ps, which is an upper evaluation of the residence time of water molecules involved in minor groove spines of hydration, but rather less than other types of water molecules trapped for instance, by amidinium groups of netropsin compounds (34).…”

Section: Discussionmentioning

confidence: 99%

Conformations of Nicked and Gapped DNA Structures by NMR and Molecular Dynamic Simulations in Water

et al. 1998

View full text Add to dashboard Cite

We have analyzed and compared the molecular structures and dynamics of DNA duplexes containing a nick or a gap of one nucleotide where the base in front of the gap is a guanine. The continuous strand has the sequence 5'(CAGAGTCXCTGGCTC) where the residue X is absent for the nick, 14-mer, and where it is a G residue for the gap. Duplexes were formed with the two corresponding 7-mers. Neither of these is phosphorylated adjacent at the nick site, but it is a good model for a single strand break. For the nick structure, the quantitative NMR data show that the global conformation is very close to canonical B-form DNA, but it displays enhanced local flexibility. For the gap structure, we observe only one species in which the extra G is well stacked into the helix. The two half-helices around this residue also show a B-form conformation. As with the nick duplex, the adjacent G imino protons show enhanced exchange with solvent. The gap does not close completely. Using distance constraints, MD calculations show that the nick conformation is very close to a duplex with no lesion but is indeed more flexible in the central part. The gapped structure shows two families of conformations. One is close to B-DNA, the other is significantly kinked at the gap which reduces the size of the cavity. We observe a spine of hydration within the cavities, similar, but of different geometry in the two cases.

show abstract

“…Upon photoactivation in the presence of molecular oxygen, the flavin chromophore oxidizes and generates oxy radicals capable of causing DNA breaks. The linkage of netropsin to a flavin chromophore leads to AT selective strand cleavage reaction (195,196). Quinone-netropsin hybrids (e.g., 52) have been also designed.…”

Section: Linkage To a Photosensitive Groupmentioning

confidence: 99%

Sequence-Specific DNA Minor Groove Binders. Design and Synthesis of Netropsin and Distamycin Analogues

1998

View full text Add to dashboard Cite

Binding of Net-Fla, a Netropsin-Flavin Hybrid Molecule, to DNA: Molecular Mechanics and Dynamics Studiesin vacuoand in Water Solution

Cited by 17 publications

References 42 publications

Solution structures of a duplex containing an adenine opposite a gap (absence of one nucleotide)

Solution structures of a duplex containing an adenine opposite a gap (absence of one nucleotide)

Conformations of Nicked and Gapped DNA Structures by NMR and Molecular Dynamic Simulations in Water

Sequence-Specific DNA Minor Groove Binders. Design and Synthesis of Netropsin and Distamycin Analogues

Contact Info

Product

Resources

About