ArticleProceedings of the National Academy of Sciences of the United States of America2025
Amino acid transfer free energies reveal thermodynamic driving forces in biomolecular condensate formation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed.
- Hydration free energy is an incomplete predictor of globular protein incorporation into condensates.Biophysical journal · 2026Article
- The emerging synergy of experimental and computational approaches for therapeutic modulation of biomolecular condensates.SLAS discovery : advancing life sciences R & D · 2026Review
- CondenSimAdapter: A Versatile Builder for Multiscale Simulations of Protein Condensates with Broad Force-Field Compatibility and Robust Dense-Phase Relaxation.Journal of chemical information and modeling · 2026Article
- Proteome-scale quantification of the interactions driving condensate formation of intrinsically disordered proteins.Nature communications · 2026Article
- Biomolecular Condensates Act as Distinct Solvation Environments That Reshape Amino Acid pJournal of the American Chemical Society · 2026Article
- Learning molecular determinants of selective small-molecule partitioning across biomolecular condensates.bioRxiv : the preprint server for biology · 2026Article
- Molecular determinants of arginine versus lysine cation-π interactions in biomolecular condensates.Communications chemistry · 2026Article
- Navigating condensate micropolarity to enhance small-molecule drug targeting.Nature chemical biology · 2026Article
- Asymmetry in Hydrophobicity Induces Electric Potential in Non-Charged Biomolecular Condensates.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Biomolecular Condensates Act as Distinct Solvation Environments that Reshape Amino Acid pKₐ Values.bioRxiv : the preprint server for biology · 2026Article
- Article
- Sequence-based prediction of condensate composition reveals that specificity can emerge from multivalent interactions among disordered regions.Communications chemistry · 2025Article
- Sequence-based prediction of condensate composition reveals that specificity can emerge from multivalent interactions among disordered regions.bioRxiv : the preprint server for biology · 2025Article
- Hydrophobicity in Intrinsically Disordered Protein Force Fields: Implications for Conformational Ensembles and Protein-Protein Interactions.The journal of physical chemistry. B · 2025Article
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Abstract
The self-assembly of intrinsically disordered proteins into biomolecular condensates depends on their primary sequence, leading to sequence-dependent phase separation. Computational methods to study this behavior often rely on residue-level interaction potentials that estimate the propensity of amino acids to partition between the dilute and dense phases. While distribution coefficients would provide the most direct measure of these potentials, their unavailability has led to the use of proxies, most notably, hydropathy. However, recent studies have highlighted limitations in hydropathy-based models. Here, we address this fundamental gap by calculating the transfer free energies for amino acid side chain analogs moving from the dilute phase to the dense phase of biomolecular condensates. We find that, net transfer free energies arise from a balance between favorable protein-mediated and unfavorable water-mediated interactions, with a striking asymmetry between the contributions of positive and negatively charged residues. This asymmetry originates from the stronger solvation of negatively charged species, and extends to modified amino acids. We further demonstrate that the sequence features of the condensate-forming protein modulate these transfer free energies in a context-dependent, but qualitatively similar manner. These findings help explain nontrivial experimental trends and provide a foundation for interpreting the sequence-dependent driving forces underlying condensate formation.
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