Long-range electrodynamic INteractions between proteinS

Project Information

LINkS

Grant agreement ID: 964203

DOI

10.3030/964203

Project closed

EC signature date 1 February 2021

Start date 1 September 2021

End date 28 February 2026

Funded under

• EXCELLENT SCIENCE - Future and Emerging Technologies (FET)

Total cost

€ 3 090 575,00

EU contribution

€ 3 090 575,00

Coordinated by

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Periodic Reporting for period 2 - LINkS (Long-range electrodynamic INteractions between proteinS)

Reporting period: 2022-09-01 to 2024-02-29

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the second reporting period (M12 to M30), partners have made significant progress on each WP:

In WP1, suitable model proteins to investigate LEDI’s activation triggered by light or chemical reactions (D1.2) have been designed and produced. Coarse-grained simulations have addressed the coupling between phonon vibrations and charge transport in long-range electrodynamic interactions and have been prioritized over forcefield based simulations (addressing only phonon vibrations). Co-resonant electronic currents in restriction enzymes interacting with cognate DNA has been evidenced (submitted article to Scientific Reports) and the first blue light pump X-ray diffraction probe experiment at the IV-MAX beam line has been carried out on bovin trypsin and on phycoerythrin.

The work carried-out on WP2 has been devoted to improvements related to the instrumentation developed during the first period of the project to reduce interference caused by parasitic THz radiation and temperature variation. Development focus was then shifted to create a system providing near-field THz spectroscopy capability. The first system is expected to be ready for use in the coming months and an improved version based on a customized THz sensor chip is expected to become operational later this year to reveal THz fingerprints of LEDIs activation.

WP3 engineered proteins by attaching specific chromophore. A novel dual-wavelength FCCS spectrophotometer for selectively exciting and probing proteins has been developed together with a coarse-grained dynamic simulations that represent interacting proteins as time-dependent electric dipoles. iScience journal has published a study on survivin's interaction with epigenetic machinery and machine learning to discern peptide composition preferences. The latter is detailed in a patent application and a bioRxiv preprint. Additionally, LINkS consortium teams conducted a time-resolved SAXS experiment focused on light-induced aggregation of R-phycoerythrin.

Regarding WP4, LINkS project has been tightly monitored by the PI throughout RP2. In terms of administrative follow up, an intermediary financial and PM follow up was set in May 2023. In terms of scientific monitoring, in addition to the WP monthly meetings, Executive Board meetings and Steering Committees, an annual session was held to gather the consortium in July 2023 with an ambitious workprogramme organized on site in Montpellier and Marseille laboratories (CNRS).

In terms of dissemination and communication (WP5), during RP2, the communication about the project was mainly done through the website and social media. Regarding the dissemination of the results, LINkS was presented in 9 scientific events, including international conferences, reaching an audience of +900 persons. In the scope of the Summer School planned in the GA, CNRS is currently organizing a workshop in Montpellier, that will be held in early July 2024.

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".

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.

TeraHertz nanotechnologies