This journal is © The Royal Society of Chemistry 2019 J. Mater. Chem. B Cite this: DOI: 10.1039/c9tb00122k Enhancing the optical detection of mutants from healthy DNA with diamondoids Chandra Shekar Sarap, * a Pouya Partovi-Azar b and Maria Fyta a DNA mutations and epigenetics have a vital role in cell development and human diseases. The identification of mutants among healthy nucleotides is indispensable and engineered nanomaterials can be an ideal platform for next-generation sequencing technology. Herein, we explore the sensitivity of memantine-thiol diamondoid in sensing and identifying modified DNA nucleotides by considering a mutation and an epigenetic marker as representative modified forms of cytosine and guanine. We demonstrate the possibility of detecting small modifications in nucleotides using optical absorption spectroscopy and charge transfer analysis. The results underline distinct features in the diamondoid– nucleotide complexes with respect to the modification in the nuclotides. A transient excitation of the complexes at certain energies obtained from their absorption spectra reveals different characteristics in the temporal evolution of the dipole moment oscillations for healthy and modified DNA nucleotides. Our study has clearly shown distinct peaks in the transformed spectra, detectable through high resolution spectroscopy studies. Accordingly, a diamondoid has high potential to optically probe chemical modifications within single DNA nucleotides, a significant aspect towards DNA sensing. Introduction DNA mutations and epigenetic modifications strongly influence the activity of genes in biological cells. 1,2 Modifications of DNA nucleotides with chemical functional groups can have a drastic impact on the overall genome function. 3,4 As an example, the presence of methylcytosine influences mammalian embryonic stem cell maintenance, angiogenesis, and its production. 5 For- feiture of regulation in epigenetic markers affects the physiology of the cell and causes hereditary problems and sometimes even cancer. 6–8 Identifying and perceiving the influence of such modified nucleotides are an important aspect in epigenetics research, 9–11 and they are the focus in targeted genome engineering. 12 Detecting DNA modifications can further allow the evaluation of sources of dis- eases, revolutionizing cancer therapy. 13–15 Despite the progressive development in DNA methylome analyses of cells and tissues, current techniques for genome-scale profiling of DNA methylation in circulating cell-free DNA remain rather limited. 4 Nanopore-based methods for methylation detection have also been developed, 16,17 but still leave room for further improvement and enhancement of the nucleotide specificity of the current signals. In view of reading-out DNA molecules, single-molecule real-time technology is a commercially available platform. 18 This can directly observe each nucleotide procured from a DNA polymerase by leveraging the speed and processivity of an enzyme. 19 Solid state nanopore devices 20–22 made of silicon- nitride, graphene, molybdenum disulfide, etc. with a suitable pore size 23 are an alternative sequencing platform for DNA. Sensing of the DNA molecules is possible when these are electrophoretically driven through the pores. 24 Detection protocols in nanopores for distinguishing different biomolecules or nucleo- tides therein involve use of the modulations in the ionic current known as current blockades, 25 electronic tunneling current measurements, 26 optical signals, 27 etc. As often these signals overlap leading to a low signal-to-noise ratio and many errors in detection, 28 alternatives have been proposed. Among them, the use of functionalized electrodes embedded in nanopores is highly endorsed. 20 A very promising functionalization towards this goal involves the use of tiny diamond-like particles, known as diamondoids. 29,30 Derivatives of small diamondoids form stable hydrogen bonds with DNA nucleotides. 31,32 Through further modification with a thiol group, these can be used to functionalize electrodes in nanopores and electronically identify DNA nucleotides and their modifications. 33,34 In order to further enhance this sequencing possibility mainly towards identifying modifications in DNA, we explored the use of optical properties arising from complexes made of the probe diamondoid and the target DNA nucleotide. We built upon our previous studies 35 on the bio-relevance of small diamondoids by probing modified and mutated DNA nucleotides. In this respect, this paper is organized as follows: we first present the methodology used in a Institute for Computational Physics, Universita ¨t Stuttgart, Allmandring 3, 70569 Stuttgart, Germany. E-mail: chandra@icp.uni-stuttgart.de b Institute of Chemistry, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 4, 06120 Halle (Saale), Germany Received 19th January 2019, Accepted 15th April 2019 DOI: 10.1039/c9tb00122k rsc.li/materials-b Journal of Materials Chemistry B PAPER Published on 17 April 2019. Downloaded by Universitat Stuttgart on 5/22/2019 8:51:18 AM. View Article Online View Journal