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Long-range electrodynamic INteractions between proteinS

Periodic Reporting for period 1 - LINkS (Long-range electrodynamic INteractions between proteinS)

Reporting period: 2021-09-01 to 2022-08-31

What are the physical forces that bring the huge number of biochemical players in cells at the right place, in the right order and in a reasonably short time to sustain cellular function and ultimately cellular life? Biology has already demonstrated how, on short distance scales (less than ten Angstroms), well known forces (e.g. Coulomb, van der Waals, etc.) drive these intermolecular interactions and explain how proteins, when they get very close to each other, end up attracting and assembling together to start reactions. An important question remaining open is: how do they get close enough to react? Are there other mechanisms beyond random “blind” movements that allow them to mutually "find each other" when and where needed? In the LINkS project, we are proposing a novel kind of Long range ElectroDynamics Interactions (LEDIs) to explain the spatial and temporal organization for efficient transmission of information in cells and their functioning.

Expanding the list of known intermolecular interactions by adding long-range force of new kind and explaining its role in the cellular machinery could lead to a paradigm-shift in biophysics and to the development of an entire segment of the biomarker industry; as it shapes biomolecular dynamics in biology.

Early stage diagnosis of diseases should have a radical societal and economic impact at the European level. Today, proteomic analysis requires expensive scanners as well as chips with limited lifetime and specific storage conditions. New thinking is needed to have a significant impact on drug discovery and new therapies. Future state-of-the-art of technological devices are needed to significantly accelerate proteomic analysis and reduce the costs of research, clinical diagnostics and drug-dosing. LINKS contributes to this with its low-cost, time-saving, high-reliability biosensor approach. European industry will benefit from LINkS technology to enable a more efficient and specific method of early disease diagnosis, thereby contributing to the creation and development of related markets.

The main objectives of LINkS are :
• To demonstrate LEDIs activation as a mechanism sustaining molecular dynamic from the molecular level to the living-cells stage.
• To develop a breakthrough a biosensor technology to investigate LEDIs between proteins.
• To exploit the participation of academic and industrial partners from different scientific backgrounds to reinforce EU Nanobioelectronics industry capabilities, boosting innovation and growth of European SMEs by opening up new possibilities for other industries
• To build leading research and innovation capacity across Europe by training the young generation of scientists in cutting-edge technologies.
During the first reporting period between M1 to M12, partners have made significant progress on each WP despite the delays and limitations due to COVID-19 pandemic.
In WP1, a first set of model proteins has been identified taking into account biological arguments and technical constraints relevant to each experimental technique of the project. This first set of protein models will be updated during the course of the project, depending on the outcome of the tests. First batches of model protein with various number of dyes/protein for with different receptors were synthesis to dissociate energy pumping from FCS measurements to separate wide field illumination (out-of-equilibrium conditions required for LEDIs activation and spot FCS recording (induced variation of the diffusion coefficient). Collective oscillations of proteins were also probed by femto-second X-ray crystallography; mapping the direction of spontaneous and THz induced/enhanced/disrupted atom displacements. A proof-of-concept experiment is actually under review at PNAS.

The work carried-out on WP2 has been devoted to the design and fabrication of the biosensor with the priority given to the reproducibility of the experiments to obtain qualitative results. Therefore, the electronic part of the sensor (FET: Field Effect Transistor) can now be reused while the low-cost microfluidic part can be discarded after each use. In this revised concept, the FET is positioned at some distance outside of the cuvette and the THz radiation is directed from the cuvette to the FET with a series of specifically designed lenses and mirrors; thus simplifying the assembly between the microfluidic and the electronics and reducing the manufacturing risks. First part of the work was carried out using CW, FTIR and THz TDS with the focus on material (polymers) characterizations (refractive indexes and absorption coefficients). In parallel, the FET performances were fully characterized in both DC and THz regime (sensitivity, sampling frequency, NEP). Several configuration microfluidic chips were designed, fabricated (using state-of-art technics) and fully-characterized. A first prototype was integrated and tests were performed revealing the potential for revealing the activation of LEDIs.

Regarding WP4, related to project coordination and management aspects, all the tasks have been implemented smoothly. Each WP leader is responsible for the scientific and technical coordination of the work plan within the WP. The administrative, legal and financial aspects are duly implemented and monitored by the Project Management Team. The submissions of contractual deliverables have been completed on time and no major issue has emerged.

In terms of dissemination and communication (WP5), LINKS is present online through various media and has contributed to major dissemination events such as the French-German TeraHertz Conference.

Main result achieved so far lies into the experimental evidence of LEDIs between in vitro proteins. It has been published in the prestigious scientific journal Science Advances (AAAS) under the title "Experimental evidence for long-distance electrodynamic intermolecular forces".
LINkS will bring innovation from one side to the fundamental knowledge on protein-protein interactions and, to the other side, to THz-devices, microfluidic architecture and process of integration. Here we describe each of them:

• Advancement beyond State-of-the-Art on fundamental knowledge on protein-protein interactions. The discovery of completely new electrodynamic forces acting between biomolecules and extending beyond several hundreds or even thousands of Angstroms has been experimentally demonstrated for the first time. Predicted since the beginning of the 20th century by classical and quantum electrodynamics, resonant electrodynamic intermolecular forces acting at a long distance had, up to now, eluded experimental detection. This is no longer the case. This discovery confirms that the activation of LEDIs only occurs when the molecules are driven out of thermal equilibrium and sheds new light on the recruitment of biomolecular reaction partners over long distances.
• State-of-the-Art on THz-biosensors will be advanced in two different directions: hardware implementations and integration. New architecture of Silicon-based electronic devices integrated withing planar broadband antennae will be developed as well as new microfluidic sealing technological processes. Technic of choice for integration in the first layer is clamping which ensure low leakage risks and high level of versatility.

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