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Phase separation of biomolecules can facilitate their spatiotemporally regulated self-assembly within living cells. Due to the selective yet dynamic exchange of biomolecules across condensate interfaces, condensates can function as reactive hubs by concentrating enzymatic components for faster kinetics. The principles governing this dynamic exchange between condensate phases, however, are poorly understood. In this work, we systematically investigate the influence of client–sticker interactions on the exchange dynamics of protein molecules across condensate interfaces. We show that increasing affinity between a model protein scaffold and its client molecules causes the exchange of protein chains between the dilute and dense phases to slow down and that beyond a threshold interaction strength, this slowdown in exchange becomes substantial. Investigating the impact of interaction symmetry, we found that chain exchange dynamics are also considerably slower when client molecules interact equally with different sticky residues in the protein. The slowdown of exchange is due to a sequestration effect, by which there are fewer unbound stickers available at the interface to which dilute phase chains may attach. These findings highlight the fundamental connection between client–scaffold interaction networks and condensate exchange dynamics.
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This content will become publicly available on April 6, 2026
Backbone-mediated weakening of pairwise interactions enables percolation in peptide-based mimics of protein condensates
Biomolecular condensates formed by intrinsically disordered proteins (IDPs) are semidilute solutions. These can be approximated as solutions of blob-sized segments, which are peptide-sized motifs. We leveraged the blob picture and molecular dynamics simulations to quantify differences between interresidue interactions in model compound and peptide-based mimics of dense versus dilute phases. The all-atom molecular dynamics simulations use a polarizable forcefield. In model compound solutions, the interactions between aromatic residues are stronger than interactions between cationic and aromatic residues. This holds in dilute and dense phases. Cooperativity within dense phases enhances pairwise interactions leading to finite-sized nanoscale clusters. The results for peptidebased condensates paint a different picture. Backbone amides add valence to the associating molecules. While this enhances pairwise inter-residue interactions in dilute phases, it weakens pair interactions in dense phases, doing so in a concentration-dependent manner. Weakening of pair interactions enables fluidization characterized by short-range order and long-range disorder. The higher valence afforded by the peptide backbone generates system-spanning networks. As a result, dense phases of peptides are best described as percolated network fluids. Overall, our results show how peptide backbones enhance pairwise interactions in dilute phases while weakening these interactions to enable percolation within dense phases.
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- Award ID(s):
- 2227268
- PAR ID:
- 10658304
- Publisher / Repository:
- Springer
- Date Published:
- Journal Name:
- Communications Chemistry
- Volume:
- 8
- Issue:
- 1
- ISSN:
- 2399-3669
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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