Periodic Reporting for period 1 - STBR (Stochastic thermodynamics of biochemical replication)
Reporting period: 2023-05-01 to 2025-04-30
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.
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.
The project combined stochastic thermodynamics and information theory to analyze proofreading mechanisms in biochemical replication. Key achievements include:
i) Quantification of Universal Thermodynamic Trade-offs
Using entropy production and fluctuation theorems, the STBR project established precise mathematical bounds on the relationship between replication speed, accuracy, and energy consumption, for general discriminatory networks, regardless of the underlying network topology or irreversible kinetics. These results extend and generalize previous work on kinetic proofreading, providing a more comprehensive understanding of the cost of biological accuracy.
ii) Development of Thermodynamic Models for Proofreading
STBR analyzed a lesser-known proofreading model, i.e. the energy-relay proofreading model, in which energy released during catalytic steps is stored and later used to drive error correction. This model challenges traditional views that separate proofreading from energy input, showing how energy flow within a system can enhance replication fidelity.The main achievement was the discovery of multiple modes of operation is the model, based on the stochastic dissipation-error Pareto trade-off, where such systems can operate in three distinct regimes. It is even able to outperform classical kinetic proofreading in certain parameter regimes.
iii) Application of Stochastic Thermodynamics to Enzyme Localization
STBR analyzed the Pareto-optimal trade-offs between dissipation, information and chemical particle flux in a simple toy model of molecular reaction-diffusion. This model is seminal to understanding localization and robustness dynamics of enzymes with a discriminatory function. It was found that the spatial localization of enzyme turnover is tightly related to the information-dissipation bound, where a system needs a particular threshold of information to be able to localize specific chemical reactions, fundamental to the discriminatory ability of KPR and related dynamics.
i) Quantification of Universal Thermodynamic Trade-offs
Using entropy production and fluctuation theorems, the STBR project established precise mathematical bounds on the relationship between replication speed, accuracy, and energy consumption, for general discriminatory networks, regardless of the underlying network topology or irreversible kinetics. These results extend and generalize previous work on kinetic proofreading, providing a more comprehensive understanding of the cost of biological accuracy.
ii) Development of Thermodynamic Models for Proofreading
STBR analyzed a lesser-known proofreading model, i.e. the energy-relay proofreading model, in which energy released during catalytic steps is stored and later used to drive error correction. This model challenges traditional views that separate proofreading from energy input, showing how energy flow within a system can enhance replication fidelity.The main achievement was the discovery of multiple modes of operation is the model, based on the stochastic dissipation-error Pareto trade-off, where such systems can operate in three distinct regimes. It is even able to outperform classical kinetic proofreading in certain parameter regimes.
iii) Application of Stochastic Thermodynamics to Enzyme Localization
STBR analyzed the Pareto-optimal trade-offs between dissipation, information and chemical particle flux in a simple toy model of molecular reaction-diffusion. This model is seminal to understanding localization and robustness dynamics of enzymes with a discriminatory function. It was found that the spatial localization of enzyme turnover is tightly related to the information-dissipation bound, where a system needs a particular threshold of information to be able to localize specific chemical reactions, fundamental to the discriminatory ability of KPR and related dynamics.
The STBR project has made significant contributions beyond existing knowledge in the field:
i) New Insights into Proofreading Mechanisms
While classical kinetic proofreading models focus on external ATP-driven energy consumption, STBR’s energy-relay proofreading model demonstrates how internal energy flows can also drive error correction and can operate in different regimes. This shifts the paradigm for understanding molecular accuracy.
ii) Generalization of Thermodynamic Trade-offs
The project derived universal scaling laws that describe how biological systems trade off accuracy, speed, and energy for general discriminatory networks, regardless of the underlying network topology or irreversible kinetics. These insights apply beyond biochemical replication to areas like protein synthesis and enzymatic reactions.
iii) Potential for Biotechnological and Biomedical Applications
The theoretical framework developed in STBR can be used to optimize synthetic biological circuits, making them more energy-efficient and accurate. Furthermore, understanding how nature balances accuracy and energy use could inspire new strategies in drug design and disease prevention.
i) New Insights into Proofreading Mechanisms
While classical kinetic proofreading models focus on external ATP-driven energy consumption, STBR’s energy-relay proofreading model demonstrates how internal energy flows can also drive error correction and can operate in different regimes. This shifts the paradigm for understanding molecular accuracy.
ii) Generalization of Thermodynamic Trade-offs
The project derived universal scaling laws that describe how biological systems trade off accuracy, speed, and energy for general discriminatory networks, regardless of the underlying network topology or irreversible kinetics. These insights apply beyond biochemical replication to areas like protein synthesis and enzymatic reactions.
iii) Potential for Biotechnological and Biomedical Applications
The theoretical framework developed in STBR can be used to optimize synthetic biological circuits, making them more energy-efficient and accurate. Furthermore, understanding how nature balances accuracy and energy use could inspire new strategies in drug design and disease prevention.