Simulation Studies on Signature Interactions between Cancer DNA and Cysteamine-Decorated AuNPs for Universal Cancer Screening

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.