In cancer genomes, DNA methylation
results in the formation of
a distinct methylation landscape (methylscape) characterized by clustered
methylation at regulatory regions separated by extensive intergenic
tracks of hypomethylated regions. This methylscape is expressed in
the majority of cancer types, thus serving as a universal biomarker
for cancer. The aim of the present study was to distinguish between
normal and cancer DNA on the basis of their distinct methylscapes
using cysteamine-capped gold nanoparticles (Cyst/AuNPs). The signature
interactions between cancer DNA and the positively charged AuNPs were
revealed by molecular dynamics (MD) simulations and density functional
theory (DFT) calculations. Our simulations demonstrate that DNA aggregates
in aqueous solution in a methylation-dependent manner, due primarily
to the increased hydrophobic force caused by the addition of the methyl
group. This suggests that the distinct methylscapes of cancer and
normal DNA may result in different agglomerations in aqueous solutions.
Cyst/AuNP adsorption patterns on normal and cancer DNA aggregates
were also observed to be distinct in MgCl2 solution. Using
MD simulations, we discovered that the backbone of oligonucleotides
plays a significant role in DNA adsorption onto the gold surface.
In addition to that, our DFT calculations indicate that 5-methylcytosine
(5-mC) adsorbed on the gold surface has a lower adsorption energy
in comparison to cytosine, suggesting that 5-mC is a more favorable
site for AuNP adsorption. Due to the methylation-dependent adsorption
of Cyst/AuNPs on DNA aggregates, this enables the use of Cyst/AuNPs
in cancer screening on the basis of the dispersion of AuNPs adsorbed
on DNA aggregates, which is consistent with our experimental validation.
This work paves the way for the development of a rapid colorimetric
AuNP-based biosensor for methylscape detection that could be used
for universal cancer screening.