Abstract
Both cytosine-Ag-cytosine interactions and cytosine modifications in a DNA duplex have attracted great interest for research. Cytosine (C) modifications such as methylcytosine (mC) and hydroxymethylcytosine (hmC) are associated with tumorigenesis. However, a method for directly discriminating C, mC and hmC bases without labeling, modification and amplification is still missing. Additionally, the nature of coordination of Ag+ with cytosine-cytosine (C-C) mismatches is not clearly understood. Utilizing the alpha-hemolysin nanopore, we show that in the presence of Ag+, duplex stability is most increased for the cytosine-cytosine (C-C) pair, followed by the cytosine-methylcytosine (C-mC) pair, and the cytosine-hydroxymethylcytosine (C-hmC) pair, which has no observable Ag+ induced stabilization. Molecular dynamics simulations reveal that the hydrogen-bond-mediated paring of a C-C mismatch results in a binding site for Ag+. Cytosine modifications (such as mC and hmC) disrupted the hydrogen bond, resulting in disruption of the Ag+ binding site. Our experimental method provides a novel platform to study the metal ion-DNA interactions and could also serve as a direct detection method for nucleobase modifications.
Highlights
Both cytosine-Ag-cytosine interactions and cytosine modifications in a DNA duplex have attracted great interest for research
Considering that cytosine (C) modifications such as 5-methylcytosine and 5-hydroxymethylcytosine are important epigenetic markers associated with gene expression and tumorigenesis[13,14,15], we were motivated to explore the interactions of Ag1 with a DNA duplex containing a single C-C, C-mC or C-hmC mismatch in the alpha-hemolysin nanopore (a-HL)
By molecular dynamics (MD) simulations, we found that cytosine modifications such as mC and hmC disrupted both the hydrogen bonds and Ag1 interactions, which subsequently affected DNA-Ag1 stability
Summary
Both cytosine-Ag-cytosine interactions and cytosine modifications in a DNA duplex have attracted great interest for research. Considering that cytosine (C) modifications such as 5-methylcytosine (mC) and 5-hydroxymethylcytosine (hmC) are important epigenetic markers associated with gene expression and tumorigenesis[13,14,15], we were motivated to explore the interactions of Ag1 with a DNA duplex containing a single C-C, C-mC or C-hmC mismatch in the alpha-hemolysin nanopore (a-HL). By molecular dynamics (MD) simulations, we found that cytosine modifications such as mC and hmC disrupted both the hydrogen bonds and Ag1 interactions, which subsequently affected DNA-Ag1 stability (in the term of rate of dissociation)
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