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DNA as a training platform for photodynamic processes in soft materials

Periodic Reporting for period 1 - LightDyNAmics (DNA as a training platform for photodynamic processes in soft materials)

Reporting period: 2018-04-01 to 2020-03-31

Light and soft matter interaction is essential to our life and to our society, being the basis of fundamental biological and technological processes, such as photosynthesis, vision, photovoltaics, and OLED displays. In order to fully master such processes, we have to understand them from the atomic level to the material scale. This is a tremendous challenge and requires the integration of many techniques, from those already existing to those newly in development, incorporating both experimental and computational approaches. The objectives of the LightDyNAmics project involve developing these methods (Work Package 1), using DNA as a training ground (Work Package 2), and applying the knowledge obtained to other multi-chromophoric systems (Work Package 3). The partners of LightDyNAmics (ten leading research institutions, three companies + seven partner organisations in nine European countries) choose to focus mainly on a single system, in order to make the transfer of knowledge between the different partners easier, which is why DNA has been selected as a training ground. The interaction between light and DNA has a fundamental biological relevance, since it can damage genetic code and lead to cellular death and cancer. At the same time, the study of this flexible multi-chromophore system allows most of the challenges ahead in this field to be tackled. In particular, our research activities aim to:
1. Develop new time-resolved experimental spectroscopic techniques with both higher temporal resolution and increased sensitivity.
2. Develop new computational methods to allow the simulation of time-resolved spectra, and to describe the excited state dynamics in multi-chromophore systems from femtoseconds to milliseconds.
3. Apply these techniques to representative DNA systems, from nucleobases to quadruple helices, also containing newly discovered epigenetic bases.
4. Develop new DNA ligands for diagnostic and therapeutic use.
At the heart of these developments are our 15 early stage researchers (ESRs) who are being trained in these multi-disciplinary approaches, cross-developing experimental and computational skills, to become the next generation of scientists, capable of contributing to this highly active area of research now and in the future.
The project officially began on 1 April 2018 and the 13 beneficiaries successfully recruited the 15 ESRs using a transparent, merit-based procedure, favouring international mobility. Within the first 24 months of the project, we have made significant progress in all of the objectives detailed above, leading to the publication of almost 30 peer-reviewed articles in world leading journals. Our LightDyNAmics ESRs have also presented their work at a number of international conferences around Europe, increasing the outreach of our project (Work Package 5). Our ESRs have received key training at the network level, in addition to the local training provided by their host institution and PhD programme (Work package 4). To this end, we have carried out three network-wide meetings: 1) an Introduction Week in Naples, Italy on “DNA Fundamentals”; 2) the 1st LightDyNAmics week in Bologna, Italy; and 3) a Technology Training Camp on “Experimental and computational spectroscopy” in Vienna, Austria. A further key component of acquiring multidisciplinary skills in the network is for the ESRs to perform secondments in other research groups, and 11 of these secondments have been carried out at present. Online training activities have also been implemented, and they will be further potentiated, which will also help to meet the additional challenges provided by the outbreak of COVID-19, which is severely hampering research mobility. All these activities try to follow one of the main training guidelines of our network, i.e. providing basic experimental training to computationally oriented students and vice-versa. The dissemination of the activities of the network has been facilitated with the creation of a dedicated website (https://www.lightdynamics.eu/) and twitter account (@lightdynamics1). We submitted all the deliverables due in the reporting period and the main milestones have been attained.
1. We have improved our ultrafast spectroscopy setups to unprecedented time resolution, and made important steps towards 2D UV spectroscopy, an as of yet undeveloped technique. In particular, for multichromophore systems many spectral signals can overlap and be difficult to distinguish, and these developments will facilitate their elucidation.
2. We made important advances in the development of computational methods, improving both our ability in describing very accurately what happens in medium size molecules on an ultrafast time-scale and correctly what happens on longer time-scale for systems containing many chromophores.
Besides their relevance for the study of DNA photodamage, the progresses at point 1 and 2 will positively impact the study of the many key biological and technological processes which are driven by the interaction with light.
3. We characterized the primary species (electrons and radicals) resulting by absorption of low energy UV photons by G-quadruplexes, i.e guanine rich regions of DNA that form four stranded quadruple helices (G4). Based on the numerous results collected during the project, we proposed a mechanism explaining this phenomenon. G4 are found in biologically functional regions of the genome, particularly those related to gene promoters and telomers, and have been implicated in DNA replication, transcription, and epigenetic modification. Our studies thus brought an important insight in the mechanism of oxidative damage to the genetic code, responsible for carcinogenesis and aging. We hope that they will also benefit the therapeutic efforts in these fields. Our findings should also inspire the development of G4-based optoelectronic devices in the field of nanotechnology.
4. We have synthesised and studied the mechanism of potential drug scaffolds and variety of fluorescent probes. These probes are likely to be of significant diagnostic and therapeutic use.
5. Last but not least, the strong expertise the ESRs and the beneficiaries are developing in the study, the handling and the modifications of oligonucleotides can have a tremendous impact on the health and medical needs of UE. Just to make an unfortunately timely example, a beneficiary (LMUM) in response to the COVID-19 crisis has started to use the synthetic oligonucleotide technologies developed in the ETN to design synthetic RNAs that can block virus proliferation and established a collaboration with leading virologists. Multiple siRNA constructs were designed, synthesized and screened, finding sequences with very promising potentialities in reducing the virus load and, therefore, to be developed into a COVID-19 medicine. Due to the high actuality and the current success we plan to further expand this research.
LightDyNAmics group at UNIBO and UNIVIE
LightDyNAmics research and future application areas