DNA-Dye-Conjugates: Conformations and Spectra of Fluorescence Probes

Beierlein, Frank R.; Palomo, Miguel Paradas; Sharapa, Dmitry I.; Zozulia, Oleksii; Mokhir, Andriy; Clark, Timothy

doi:10.1371/journal.pone.0160229

Cited by 7 publications

(3 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Methyl-cytosine (mC) and its oxidized derivatives 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), and 5-carboxymethylcytosine (caC) were parametrized following a protocol previously established. ,, For the modified bases (and the C1′/H1′ atoms; the charges of all other nucleotide atoms were kept identical to their parmbsc1 values), we used RESP , charges based on quantum chemical calculations (HF/6-31G(d)//B3LYP/6-31G(d); − optimizations were performed in polarizable continuum model (PCM) water) , with Gaussian 16 in agreement with the Amber force fields. , Missing force field parameters of the bases were amended using values from Gaff (version 1.81) , or parmbsc1/ff14SB. , The DNA part of the system was described by the parmbsc1 force field and the protein by ff14SB …”

Section: Methodsmentioning

confidence: 99%

Oxidation Enhances Binding of Extrahelical 5-Methyl-Cytosines by Thymine DNA Glycosylase

2022

View full text Add to dashboard Cite

The DNA repair protein thymine DNA glycosylase (TDG) removes mispaired or damaged bases, such as oxidized methyl-cytosine, from DNA by cleavage of the glycosidic bond between the sugar and the target base flipped into the enzyme’s active site. The enzyme is active against formyl-cytosine and carboxyl-cytosine, whereas the lower oxidized hydroxymethyl-cytosine and methyl-cytosine itself are not processed by the enzyme. Molecular dynamics simulations with thermodynamic integration of TDG complexed to DNA carrying one of four different (oxidized) methyl-cytosine bases in extrahelcial conformation, methyl-cytosine (mC), hydroxymethyl-cytosine (hmC), formyl-cytosine (fC), or carboxyl-cytosine (caC), show a more favorable binding affinity of the higher oxidized forms, fC and caC, than the nonsubstrate bases hmC and mC. Despite rather comparable, reaction-competent conformations of the flipped bases in the active site of the enzyme, more and stronger interactions with active site residues account for the preferred binding of the higher oxidized bases. Binding of the negatively charged caC and the neutral fC are strengthened by interactions with positively charged His151. Our calculated proton affinities find this protonation state of His151 the preferred one in the presence of caC and conceivable in the presence of fC as well as increasing the binding affinity toward the two bases. Discrimination of the substrate bases is further achieved by the backbone of Tyr152 that forms a strong hydrogen bond to the carboxyl and formyl oxygen atoms of caC and fC, respectively, a contact that is completely lacking in mC and much weaker in hmC. Overall, our computational results indicate that the enzyme discriminates the different oxidation forms of methyl-cytosine already at the formation of the extrahelical complexes.

show abstract

Section: Methodsmentioning

confidence: 99%

Oxidation Enhances Binding of Extrahelical 5-Methyl-Cytosines by Thymine DNA Glycosylase

2022

View full text Add to dashboard Cite

show abstract

“…The different modifications, XC = CAC, FC, HMC, MC and imino tautomers XC = ICC, IFC, IHC, IMC, have been build by adding a (oxidised) methyl group to the 5C of the cytosine base of the central G:C pair. Molecular dynamics simulations of the models were performed with Amber 18 [ 32 ] and Amber 20 [ 33 ] using pmemd.cuda, following a protocol established previously [ 34 , 35 , 36 , 37 ]. The DNA part of the system was described by the parmbsc1 [ 38 ] force field and the protein by ff14SB [ 39 ].…”

Section: Methodsmentioning

confidence: 99%

“…5-Methylcytosine (MC) and its oxidised derivatives 5-hydroxymethylcytosine (HMC), 5-formylcytosine (FC) and 5-carboxylcytosine (CAC) and their imino tautomers ICC, IFC, IHC and IMC (one hydrogen moved to N3 from N4, see Figure 2 ) were parameterised following a protocol established previously [ 35 , 36 , 37 , 42 , 43 ]. Therefore, only a short summary is given here.…”

Section: Methodsmentioning

confidence: 99%

Interaction of Thymine DNA Glycosylase with Oxidised 5-Methyl-cytosines in Their Amino- and Imino-Forms

2021

View full text Add to dashboard Cite

Thymine DNA Glycosylase (TDG) is an enzyme of the base excision repair mechanism and removes damaged or mispaired bases from DNA via hydrolysis of the glycosidic bond. Specificity is of high importance for such a glycosylase, so as to avoid the damage of intact DNA. Among the substrates reported for TDG are mispaired uracil and thymine but also formyl-cytosine and carboxyl-cytosine. Methyl-cytosine and hydroxylmethyl-cytosine are, in contrast, not processed by the TDG enzyme. We have in this work employed molecular dynamics simulations to explore the conformational dynamics of DNA carrying a formyl-cytosine or carboxyl-cytosine and compared those to DNA with the non-cognate bases methyl-cytosine and hydroxylmethyl-cytosine, as amino and imino tautomers. Whereas for the mispairs a wobble conformation is likely decisive for recognition, all amino tautomers of formyl-cytosine and carboxyl-cytosine exhibit the same Watson–Crick conformation, but all imino tautomers indeed form wobble pairs. The conformational dynamics of the amino tautomers in free DNA do not exhibit differences that could be exploited for recognition, and also complexation to the TDG enzyme does not induce any alteration that would indicate preferable binding to one or the other oxidised methyl-cytosine. The imino tautomers, in contrast, undergo a shift in the equilibrium between a closed and a more open, partially flipped state, towards the more open form upon complexation to the TDG enzyme. This stabilisation of the more open conformation is most pronounced for the non-cognate bases methyl-cytosine and hydroxyl-cytosine and is thus not a likely mode for recognition. Moreover, calculated binding affinities for the different forms indicate the imino forms to be less likely in the complexed DNA. These findings, together with the low probability of imino tautomers in free DNA and the indifference of the complexed amino tautomers, suggest that discrimination of the oxidised methyl-cytosines does not take place in the initial complex formation.

show abstract

DNA Transformations for Diagnosis and Therapy

Ahn

Liu

Vellampatti

et al. 2020

Adv Funct Materials

View full text Add to dashboard Cite

Due to its unique physical and chemical characteristics, DNA, which is known only as genetic information, has been identified and utilized as a new material at an astonishing rate. The role of DNA has increased dramatically with the advent of various DNA derivatives such as DNA–RNA, DNA–metal hybrids, and PNA, which can be organized into 2D or 3D structures by exploiting their complementary recognition. Due to its intrinsic biocompatibility, self‐assembly, tunable immunogenicity, structural programmability, long stability, and electron‐rich nature, DNA has generated major interest in electronic and catalytic applications. Based on its advantages, DNA and its derivatives are utilized in several fields where the traditional methodologies are ineffective. Here, the present challenges and opportunities of DNA transformations are demonstrated, especially in biomedical applications that include diagnosis and therapy. Natural DNAs previously utilized and transformed into patterns are not found in nature due to lack of multiplexing, resulting in low sensitivity and high error frequency in multi‐targeted therapeutics. More recently, new platforms have advanced the diagnostic ability and therapeutic efficacy of DNA in biomedicine. There is confidence that DNA will play a strong role in next‐generation clinical technology and can be used in multifaceted applications.

show abstract

DNA-Dye-Conjugates: Conformations and Spectra of Fluorescence Probes

Cited by 7 publications

References 92 publications

Oxidation Enhances Binding of Extrahelical 5-Methyl-Cytosines by Thymine DNA Glycosylase

Oxidation Enhances Binding of Extrahelical 5-Methyl-Cytosines by Thymine DNA Glycosylase

Interaction of Thymine DNA Glycosylase with Oxidised 5-Methyl-cytosines in Their Amino- and Imino-Forms

DNA Transformations for Diagnosis and Therapy

Contact Info

Product

Resources

About