Theory for sequence selection via phase separation and oligomerization

TL;DR

This paper develops a thermodynamic model showing how phase separation influences sequence selection in oligomerization, suggesting condensed phases could facilitate evolutionary processes relevant to the origin of life.

Contribution

It introduces a non-equilibrium thermodynamic framework demonstrating how phase separation can drive sequence selection during oligomerization, highlighting the role of fragmentation rates.

Findings

Phase separation enhances specific sequence enrichment.

Slow fragmentation favors cooperative, alternating sequences.

Fast fragmentation selects sequences with extended motifs.

Abstract

Non-equilibrium selection pressures were proposed for the formation of oligonucleotides with rich functionalities encoded in their sequences, such as catalysis. Since phase separation was shown to direct various chemical processes, we ask whether condensed phases can provide mechanisms for sequence selection. To answer this question, we use non-equilibrium thermodynamics and describe the reversible oligomerization of different monomers to sequences at non-dilute conditions prone to phase separation. We find that when sequences oligomerize, their interactions give rise to phase separation, boosting specific sequences' enrichment and depletion. Our key result is that phase separation gives rise to a selection pressure for the oligomerization of specific sequence patterns when fragmentation maintains the system away from equilibrium. Specifically, slow fragmentation favors alternating sequences that interact well with their environment (more cooperative), while fast fragmentation selects sequences with extended motifs capable of specific sequence interactions (less cooperative). Our results highlight that out-of-equilibrium condensed phases could provide versatile hubs for Darwinian-like evolution toward functional sequences, both relevant for the molecular origin of life and de novo life.