Blockiness as Determinant of Liquid Phase Formation by Polypeptide-Like Polymers in Stickers-Spacers Paradigm
- 1Skolkovo Institute of Science and Technology
Abstract
Liquid-liquid phase separation (LLPS) driven by intrinsically disordered protein regions underlies the formation of membraneless organelles. The role of these structures in cell biology is an active area of research, yet their physical understanding remains less developed than that of protein assemblies with well-defined, rigid tertiary structures. The amino acid composition of disordered regions, particularly the abundance of charged residues, is known to modulate phase behavior. These factors govern accessible conformations, the assembly of compact sticker clusters, and the porosity of the resulting polymer networks. In contrast, the spatial distribution of side-chain volumes remains a comparatively understudied sequence determinant. Here, we employ a model that captures the patterning of side-chain volumes and interaction strengths without specifying chemical identity to show how sequence blockiness modulates the phase-nucleation propensity, connectivity, and compactness of polypeptide-like polymer assemblies. Using a library of polymers with identical composition but permuted residue arrangements, we show that clustering of bulky residues generates cooperative sticker domains and identify the threshold blockiness required to stabilize polymer networks. Coarse-grained simulations and mean-field theory reveal that this effect arises from an interplay among steric repulsion, solvent entropy, and higher-valency interactions, whereby blocky patterns promote the formation of multi-node percolated networks. Segregation of stickers and spacers is therefore one of the sequence parameters governing LLPS which may be useful for interpreting the evolution of disordered protein sequences, high-throughput proteome screening, and engineering of stimuli-responsive biomaterials. These rules may be exploited to predetermine condensate stability, viscoelasticity, and molecular exchange rates without altering chemical functionality.
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BibTeX
@misc{vasilenko2026blockiness,
title = {{Blockiness as Determinant of Liquid Phase Formation by Polypeptide-Like Polymers in Stickers-Spacers Paradigm}},
author = {E. O. Vasilenko and D. S. Belous and D. N. Ivankov},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.756799},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756799v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Blockiness as Determinant of Liquid Phase Formation by Polypeptide-Like Polymers in Stickers-Spacers Paradigm
AU - E. O. Vasilenko
AU - D. S. Belous
AU - D. N. Ivankov
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.756799
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.756799v1
AB - Liquid-liquid phase separation (LLPS) driven by intrinsically disordered protein regions underlies the formation of membraneless organelles. The role of these structures in cell biology is an active area of research, yet their physical understanding remains less developed than that of protein assemblies with well-defined, rigid tertiary structures. The amino acid composition of disordered regions, particularly the abundance of charged residues, is known to modulate phase behavior. These factors govern accessible conformations, the assembly of compact sticker clusters, and the porosity of the resulting polymer networks. In contrast, the spatial distribution of side-chain volumes remains a comparatively understudied sequence determinant. Here, we employ a model that captures the patterning of side-chain volumes and interaction strengths without specifying chemical identity to show how sequence blockiness modulates the phase-nucleation propensity, connectivity, and compactness of polypeptide-like polymer assemblies. Using a library of polymers with identical composition but permuted residue arrangements, we show that clustering of bulky residues generates cooperative sticker domains and identify the threshold blockiness required to stabilize polymer networks. Coarse-grained simulations and mean-field theory reveal that this effect arises from an interplay among steric repulsion, solvent entropy, and higher-valency interactions, whereby blocky patterns promote the formation of multi-node percolated networks. Segregation of stickers and spacers is therefore one of the sequence parameters governing LLPS which may be useful for interpreting the evolution of disordered protein sequences, high-throughput proteome screening, and engineering of stimuli-responsive biomaterials. These rules may be exploited to predetermine condensate stability, viscoelasticity, and molecular exchange rates without altering chemical functionality.
ER -