[Paper Review] A minimal scenario for the origin of non-equilibrium order

Riccardo Ravasio, Kabir Husain+5 more|PubMed|May 17, 2024

Evolution and Genetic DynamicsBiochemistry, Genetics and Molecular Biology3 citations

TL;DR

This paper proposes that non-equilibrium order in self-replicating systems arises not through direct selection for order, but as an inevitable byproduct of selection for fast replication when replication times exhibit high variance. By modeling polymerases and self-assembly with stalling effects, the authors show that kinetic proofreading and structural order emerge spontaneously due to slowdowns from geometric frustration, leading to faster replication and dominance in populations even without functional benefits to the order.

ABSTRACT

Life uses non-equilibrium mechanisms to create ordered structures not attainable at equilibrium; the resulting order is assumed to provide functional benefits that outweigh costs of time and energy needed by these mechanisms. Here, we show that models of DNA replication and self-assembly, when expanded to include known stalling effects, can evolve error correcting mechanisms like kinetic proofreading and dynamic instability through selection for fast replication alone. We abstract these results into a general framework that predicts a counterintuitive ''order through speed'' effect if the distribution of replication times is wide enough. We test our results against recent mutational screens of proofreading polymerases. Our work suggests the intriguing possibility that non-equilibrium order can evolve even before that order is directly functional, with consequences for the evolution of mutation rates, viral capsid assembly, and the origin of life.

Motivation & Objective

• To investigate whether non-equilibrium order can emerge spontaneously in self-replicating systems without direct selection for order.
• To examine how stalling during templated replication and self-assembly influences the evolution of error-correcting mechanisms.
• To determine the minimal conditions under which order-enhancing mechanisms evolve due to selection for replication speed alone.
• To abstract a general principle linking replication time variance to the spontaneous emergence of dissipative order.
• To explore implications for the origin of life, enzyme fidelity, and self-assembly dynamics.

Proposed method

• Modeling DNA polymerases with stalling effects due to misincorporation, incorporating kinetic proofreading as a mechanism to improve fidelity.
• Extending the model to include replication time distributions with high variance, simulating the impact of geometric frustration and conformational search in high-dimensional spaces.
• Analyzing multicomponent self-assembly processes where misincorporation induces delays, leading to selection for non-equilibrium checkpoint mechanisms.
• Using statistical mechanics and non-equilibrium dynamics to formalize the relationship between replication speed, error correction, and order enhancement.
• Abstracting the core principle: when replication time variance is large, systems with order-enhancing mechanisms replicate faster and dominate.
• Applying the framework to diverse systems, including ribozymes, viral capsids, and ribosomes, to test generality across biological contexts.

Experimental results

Research questions

• RQ1 Can non-equilibrium order emerge in self-replicating systems even when the order provides no direct fitness benefit?
• RQ2 How do stalling effects during replication or self-assembly lead to the spontaneous evolution of kinetic proofreading and structural order?
• RQ3 What role does the variance in replication times play in selecting for order-enhancing mechanisms?
• RQ4 Under what conditions does selection for fast replication alone lead to the emergence of dissipative order?
• RQ5 Can this mechanism explain the evolution of high-fidelity replication and complex self-assembly without assuming functional advantages of order?

Key findings

• Systems with higher replication speed due to stalling-induced error correction (e.g., kinetic proofreading) outcompete others even when the order is not functionally beneficial.
• The distribution of replication times must have sufficient variance for order-enhancing mechanisms to be selected, with high variance amplifying the advantage of error-correcting processes.
• In polymerase models, stalling upon misincorporation leads to faster overall replication when proofreading is present, due to reduced time spent on non-productive paths.
• In self-assembly, geometric frustration and misincorporation-induced pauses select for non-equilibrium checkpoint mechanisms that increase structural order without direct functional selection.
• The counter-intuitive speed-accuracy relationship arises because error correction reduces the entropy of replication pathways, effectively canalizing them into faster, more ordered trajectories.
• This mechanism provides a plausible route for the spontaneous emergence of error-correcting ribozymes and high-fidelity enzymes in prebiotic systems, even before functional roles for order emerged.