Reviewer #2 (Public review): Electrostatics of Salt-Dependent Reentrant Phase Behaviors Highlights Diverse Roles of ATP in Biomolecular Condensates
Bibliographic record
Abstract
Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- and ATP-dependent LLPSs of an IDR of messenger RNA-regulating protein Caprinl and its phosphorylated variant pY-Caprinl, exhibiting, e.g., reentrant behaviors in some instances but not others. Experimental data are rationalized by physical modeling using analytical theory, molecular dynamics, and polymer field-theoretic simulations, indicating that interchain ion bridges enhance LLPS of polyelectrolytes such as Caprinl and the high valency of ATP-magnesium is a significant factor for its colocalization with the condensed phases, as similar trends are observed for other IDRs. The electrostatic nature of these features complements ATP’s involvement in π-related interactions and as an amphiphilic hydrotrope, underscoring a general role of biomolecular condensates in modulating ion concentrations and its functional ramifications.A major contributing mechanism in the assembly of biomolecular condensates is liquidliquid phase separation. Here, a combined experimental-theoretical approach elucidates how phase behaviors of intrinsically disordered protein regions (IDRs) are affected by their amino acid sequences—including charge, aromatic and phosphorylation patterns—as well as ATP and the valencies of salt ions in the aqueous milieu. Significant electrostatic effects are highlighted by the consistency between our theoretical and experimental results for an IDR of translation-regulating protein Caprin1, including strong partitioning of ATP into the Caprinl condensate. This physical perspective and the efficient computational approaches developed here should offer general insights into condensates scaffolded by polyampholytic and polyelectrolytic IDRs, including their potential functional role in regulating ion concentrations for biochemical reactions.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.028 | 0.153 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.003 |
| Bibliometrics | 0.004 | 0.002 |
| Science and technology studies | 0.003 | 0.002 |
| Scholarly communication | 0.008 | 0.005 |
| Open science | 0.006 | 0.004 |
| Research integrity | 0.020 | 0.009 |
| Insufficient payload (model declined to judge) | 0.081 | 0.043 |
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".