Departments

Project Code: N1-0300

Duration: 2023 – 2025

Project Leader: Dr. Jure Borišek

1. PROJECT DESCRIPTION 

With the aging of the global population, the burden on socio-economic and healthcare systems is intensifying. This demands effective solutions for this major challenge of our time, as aging is a key driver in the development of numerous chronic age-related diseases. Enhancing the immune system's ability to successfully clear senescent cells—one of the hallmarks of aging—would open new avenues and enable the development of novel treatments for age-related diseases. Senotherapy, a therapeutic intervention specifically targeting senescent cells, would thus extend healthy life expectancy (the number of years a person lives in a healthy state, free from severe or moderate health issues) and represent a major step forward for our aging society. Achieving this goal requires a broader understanding of the atomic-level details of the immunological surveillance of senescent cells by natural killer (NK) cells of the immune system.

In the dynoIMMUNE project, we will elucidate the atomic details of senescent cell recognition by natural killer (NK) cells of the immune system using large-scale, all-atom simulations of the inhibitory (NKG2A/CD94/HLA-E) and activating (NKG2D/DAP10/MICA) immune complexes, alongside artificial intelligence-based tools for 3D protein structure prediction. In recent years, available computational power has greatly increased, leading to tremendous progress in molecular simulations of increasingly large biological systems at the atomic level. This will enable us to gain insights into signal transduction and conformational changes that were completely inaccessible just a few years ago. The computed dynamic models will facilitate a broader understanding of the atomic details governing the molecular recognition process and will form the basis for developing new molecular approaches that can act as immune system enhancers. The knowledge gained in this project through molecular dynamics simulations will provide a foundation for developing novel therapeutic approaches to enhance the immune system. This could offer several advantages over more traditional senolytics and senomorphics, as boosting the immune response against senescent cells could lead to their comprehensive, efficient, and direct clearance in a highly controlled manner. Understanding and modulating this aspect of immune surveillance could open numerous opportunities in other research fields, such as vaccine development, the treatment of autoimmune diseases, organ transplantation, and cancer therapy.

Participating organizations: -

a. Basic funding information:

The project is funded by ARIS (Slovenian Research and Innovation Agency) under price category A for a duration of two years, with an allocation of 1,376 annual hours. Funding commenced on 1 February 2023.

b. Composition of the project team with links to SICRIS

At the National Institute of Chemistry, the project team includes:

2. PROJECT PHASES AND THEIR IMPLEMENTATION

I. Obtaining a dynamic model of the inhibitory immune complex.
II. Obtaining a dynamic model of the activating immune complex.

Implementation (April 2024):

The project is proceeding according to the planned schedule. So far, we have successfully characterized the dynamic model of the inhibitory immune complex. We have also expanded our research to study membrane composition and its impact on signal transduction within the immune complex.

Implementation (December 2025):

In the second phase, we used molecular dynamics simulations to investigate how various lipid membrane compositions affect the conformational dynamics and signal transduction of the NKG2A/CD94 receptor complex. We demonstrated that membrane composition significantly influences the behavior of the intracellular domain of NKG2A, and consequently, its ability to transmit the inhibitory signal. Furthermore, we developed and validated the application of a water-based pharmacophore modeling method, which has the advantage of being independent of known ligands and serves as an effective tool for identifying novel chemotypes. Using this approach, we identified novel inhibitors of Fyn and Lyn kinases, opening new possibilities for the development of senolytic agents and cancer treatments.

As part of the project, we made a strategic decision to prioritize our research capacity toward an in-depth study of the dynamic model of the inhibitory immune complex and its modulation. Two key reasons guided this shift: first, more high-quality structural data were available, enabling more precise models; and second, the inhibition of this system offers greater translational potential, as it allows for a direct impact on the more efficient clearance of senescent and cancer cells. Because we wished to investigate this promising system in greater detail (as demonstrated by the results achieved for the first objective), we did not pursue the study of the activating immune complex within this project; instead, it will serve as the starting point for our future research.

3. BIBLIOGRAPHIC REFERENCES ARISING DIRECTLY FROM THE IMPLEMENTATION OF THE PROJECT

1. LJUBIČ, Martin, SOLLNER DOLENC, Marija, BORIŠEK, Jure, PERDIH, Andrej. Water-based pharmacophore modeling in kinase inhibitor design : a case study on fyn and lyn protein kinases. Journal of chemical information and modeling. 2025, 65, 18, 9747−9761. dx.doi.org/10.1021/acs.jcim.5c01478

2. LJUBIČ, Martin, PERDIH, Andrej, BORIŠEK, Jure. All-atom simulations reveal the effect of membrane composition on the signaling of the NKG2A/CD94/HLA-E immune receptor complex. Journal of chemical information and modeling. 2024, 64, 24, 9374–9387. 10.1021/acs.jcim.4c01357

3. LJUBIČ, Martin, PRAŠNIKAR, Eva, PERDIH, Andrej, BORIŠEK, Jure. All-atom simulations reveal the intricacies of signal transduction upon binding of the HLA-E ligand to the transmembrane inhibitory CD94/NKG2A receptor. Journal of chemical information and modeling. 2023, 63, 11, 3486-3499. 10.1021/acs.jcim.3c00249

4. LOGOS OF ARIS AND OTHER CO-FUNDERS