Tie-Line Analysis Reveals Interactions Driving Heteromolecular Condensate Formation
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Bibliographic record
Abstract
Phase separation of biomolecules gives rise to membraneless organelles that contribute to the spatiotemporal organization of the cell. In most cases, such biomolecular condensates contain multiple components, but the manner in which interactions between components control the stability of condensates have remained challenging to elucidate. Here, we develop an approach to determine tie-line gradients in ternary biomolecular phase-separation systems based on measurements of the dilute phase concentration of only one component. We show that the sign of the tie-line gradient is related to the cross-interaction energy between the polymers in the system and discriminates between associative and segregative phase separation. Using this approach, we study the interaction between protein fused in sarcoma (FUS) and polyethylene glycol (PEG) polymer chains and measure positive tie-line gradients. Our results show that PEG drives phase separation through an associative interaction with FUS, other than through acting as an inert crowder. We further study the interaction between poly(A) ribonucleic acid (RNA) (700-3500 kDa [kilodalton]) and the protein G3BP1, and using the tie-line gradient as a reporter for the stoichiometry of polymers in the condensate, we determine a G3BP1-to-poly(A) RNA molar ratio of 10.003-0.015 in the dense phase. Our framework for measuring tie-line gradients opens up a route for the characterization of interaction types and compositions in ternary phase-separation systems.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it