Amino Acid Transfer Free Energies Reveal Thermodynamic Driving Forces in Biomolecular Condensate Formation DOI Creative Commons
Shiv Rekhi, Jeetain Mittal

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 5, 2024

The self-assembly of intrinsically disordered proteins into biomolecular condensates shows a dependence on the primary sequence protein, leading to sequence-dependent phase separation. Methods investigate this separation rely effective residue-level interaction potentials that quantify propensity for residues remain in dilute versus dense phase. most direct measure these are distribution coefficients different amino acids between two phases, but due lack availability coefficients, proxies, notably hydropathy, have been used. However, recent work has demonstrated limitations assumption hydropathy-driven In work, we address fundamental gap by calculating transfer free energies associated with transferring each acid side chain analog from model condensate. We uncover an interplay favorable protein-mediated and unfavorable water-mediated contributions overall transfer. further asymmetry positive negative charges driving forces condensate formation. results presented provide explanation several non-trivial trends observed literature will aid interpretation experiments aimed at elucidating underlying formation condensates.

Language: Английский

Sequence-based prediction of intermolecular interactions driven by disordered regions DOI
Garrett M. Ginell, Ryan J. Emenecker, Jeffrey M. Lotthammer

et al.

Science, Journal Year: 2025, Volume and Issue: 388(6749)

Published: May 22, 2025

Intrinsically disordered regions (IDRs) in proteins play essential roles cellular function. A growing body of work has shown that IDRs often interact with partners a manner does not depend on the precise order amino acids but is instead driven by complementary chemical interactions, leading to bound-state complexes. However, these chemically specific dynamic interactions are difficult predict. In this study, we repurposed physics developed originally for molecular simulations predict specificity between and partner using protein sequence as only input. Our approach-FINCHES-enables direct prediction phase diagrams, identification interaction hotspots IDRs, decomposition distinct domains route develop test mechanistic hypotheses regarding IDR function recognition.

Language: Английский

Citations

0
Amino Acid Transfer Free Energies Reveal Thermodynamic Driving Forces in Biomolecular Condensate Formation DOI Creative Commons
Shiv Rekhi, Jeetain Mittal

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 5, 2024

The self-assembly of intrinsically disordered proteins into biomolecular condensates shows a dependence on the primary sequence protein, leading to sequence-dependent phase separation. Methods investigate this separation rely effective residue-level interaction potentials that quantify propensity for residues remain in dilute versus dense phase. most direct measure these are distribution coefficients different amino acids between two phases, but due lack availability coefficients, proxies, notably hydropathy, have been used. However, recent work has demonstrated limitations assumption hydropathy-driven In work, we address fundamental gap by calculating transfer free energies associated with transferring each acid side chain analog from model condensate. We uncover an interplay favorable protein-mediated and unfavorable water-mediated contributions overall transfer. further asymmetry positive negative charges driving forces condensate formation. results presented provide explanation several non-trivial trends observed literature will aid interpretation experiments aimed at elucidating underlying formation condensates.

Language: Английский

Citations

0