STBR · Stochastic thermodynamics of biochemical replication
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2023-05-01 → 2025-04-30
- EU contribution
- €230,774
- Participants
- 1
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
Stochastic thermodynamics of biochemical replication
Biochemical replication is a fundamental process in living systems, governing how for instance genetic information is copied with remarkable precision despite the stochastic nature of molecular interactions. Understanding the thermodynamic constraints of this process is crucial for fields ranging from molecular biology to synthetic biology and biotechnology. The Stochastic Thermodynamics of Biochemical Replication (STBR) project aimed to develop a rigorous theoretical framework to describe the energy, speed, and accuracy trade-offs in biochemical copying mechanisms such as kinetic proofreading (KPR) and conformational proofreading (CPR). The broader motivation behind the project lies in the need to reconcile biological accuracy with thermodynamic efficiency. Biological systems must balance the high fidelity of replication with the limited energy resources available in the cell, as well as the robustness and localization of such processes. The project’s goal was to quantify these trade-offs, providing new insights into how nature optimizes biochemical processes under physical constraints. The pathway to impact extends beyond theoretical insights: i) The project's findings contribute to biotechnological applications, such as optimizing enzyme design in synthetic biology. ii) The research informs biomedical sciences, helping to understand diseases linked to errors in molecular copying processes. iii) The results support advances in computational biology, providing models that predict the efficiency of various proofreading mechanisms. By providing a mathematically grounded and experimentally relevant understanding of biochemical replication, STBR helps tackle fundamental scientific questions while opening new possibilities for technological applications.
Data: CORDIS, © European Union
Project objective
The main goal of this project will be to construct a thermodynamically consistent comprehensive model for biochemical replication using stochastic thermodynamics and control theory.I will subjugate the process of kinetic proofreading (KPR) to several thermodynamic bounds that have recently been discovered, in order to study the thermodynamic performance of this process. This will be done by considering the process as a chemical reaction network where a sequence of irreversible steps consume energy to increase replication accuracy and are hence bounded by fundamental no-go theorems such as the thermodynamic uncertainty relation (TUR) or the thermodynamic speed limit (TSL). I then investigate how the topology and reaction rates of the KPR network can be optimized with respect to error rate and dissipation by means of machine learning, to deduce how close biological systems operate to these bounds. Subsequently, I will extend the results to the conformational proofreading (CPR) process, where an energy handicap is added to the free energy to increase binding specificity at the expense of binding affinity. The CPR is a proofreading scheme that does not consume energy by burning ATP/GTP, so the entropy production has its origin in the conformational change.Finally, I test the robustness of the aforementioned KPR and CPR networks. In realistic systems, the kinetic rates can fluctuate as a consequence of e.g., temperature or chemical density variations, which can possibly destabilize the network and lead to more errors in the replication process. This will be done by considering the networks as input-output systems that can be studied by control theory. This provides fundamental bounds such as Bode's sensitivity integral to complement the TUR and TSL. I expect that the research results will lead to a better understanding of the fundamental limits on error correction in biological systems and will inspire further research in biophysics and structural biology.
Original text from CORDIS.
Participants
- KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark
Links
- View on CORDIS
- DOI: 10.3030/101104602
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e501fc732f&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e51abcec99&appId=PPGMS
Data: CORDIS, © European Union