The study of interactions between Au nanostructures and living cells is a fundamental aspect that can be applied for promising applications in nanomedicine. In the present work, we performed coarse-grained molecular dynamics (MD) simulations to observe the internalization pathways of Au nanostructures (nanospheres, nanocages, nanorods, nanoplates, and nanohexapods) into an idealized mammalian plasma membrane at an unprecedented level of complexity. Compared with a simple lipid bilayer model consisting of two lipid species, the different cellular uptake pathways of the gold nanoparticle (AuNP) were found. We highlight that the complexity of the lipid bilayer models plays an important role in the uptake pathway of nanoparticles (NPs). The permeability of aggregated AuNPs was much less than the NP counterpart. Spherical AuNPs showed pronounced size and surface charge dependence in their translocation through the plasma membrane. The translocation rates of different Au nanostructures were also evaluated, and we found that the Au nanohexapod exhibited highest cellular uptake. Understanding the interrelationship between size, shape, surface charge, and aggregation of Au nanostructures provides a clear view on the design of Au nanostructures for developing new diagnostic strategies and drug delivery.

A surface modification of nanoparticles (NPs) provides an effective way to control their interactions with living cells. The complete understanding of interactions between NPs and a cell membrane is a key step for the development of drug delivery. In the present work, the role of different surface charges (anionic, cationic, and zwitterionic) on the internalization through an idealized plasma membrane was investigated using a coarse-grained molecular dynamics (CGMD) technique. The decorated AuNPs used in this in silico study closely imitated those experimentally synthesized, while the idealized plasma membrane model resembled that found in living cells. The mechanism of direct translocation of a 2 nm particle by membrane was observed. The zwitterionic AuNP demonstrates a higher free-energy barrier than the positively and negatively charged AuNPs, resulting in a lack of preference for internalization across the membrane, leading to lower translocation rate and permeability of internalization. Despite the surface coverage, the agglomeration of AuNPs in a physiological condition has been observed resulting in slow unfavorable permeability. Our study highlights that in addition to surface charges, the hydrodynamic size (D H) plays an important role in the permeability of the functionalized AuNPs into the cell membrane. Through our simulations, complete understanding of interactions between ligands-coated AuNPs and the realistic plasma membrane has been established serving as a platform for the novel design of AuNPs in nanomedicine applications.

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.