Protein-RNA phase separation gives rise to biomolecular condensates with rich internal organization, yet the molecular rules that connect sequence-encoded interactions to the emergent condensate spatial organization remain poorly understood. Here, using large-scale residue-level coarse-grained simulations, we identify a molecular grammar that governs the formation of multiphase protein-RNA condensates. We show that asymmetries in protein-protein and protein-RNA interactions, together with protein stoichiometry, chain length, and condensate density, collectively determine whether condensates adopt homogeneous, layered, biphasic, or vesicle-like morphologies. Vesicular condensates form spontaneously from well-mixed initial conditions without requiring flux-driven oversaturation or extreme charge imbalance, distinguishing this mechanism from previously proposed routes to condensate hollowing. We rationalize the full morphological progression as sequence-encoded amphiphile self-assembly: the protein-RNA complex behaves as a single-chain amphiphile whose effective packing parameter is set by Domain H/L stoichiometry, spanning micelles, cylinders, hollow vesicles, and inverse phases.
Abstract
Journal Article
eng
42358691
Ramachandran, Vysakh, and Davit A. Potoyan. "A Molecular Grammar for Programmable Multiphase Protein-RNA Vesicles." JACS Au, vol. 6, no. 6, 2026, pp. 3310-3322.
Ramachandran V, Potoyan DA. A Molecular Grammar for Programmable Multiphase Protein-RNA Vesicles. JACS Au. 2026;6(6):3310-3322.
Ramachandran, V., & Potoyan, D. A. (2026). A Molecular Grammar for Programmable Multiphase Protein-RNA Vesicles. JACS Au, 6(6), 3310-3322. https://doi.org/10.1021/jacsau.6c00322
Ramachandran V, Potoyan DA. A Molecular Grammar for Programmable Multiphase Protein-RNA Vesicles. JACS Au. 2026 Jun 22;6(6):3310-3322. PubMed PMID: 42358691.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR
T1 - A Molecular Grammar for Programmable Multiphase Protein-RNA Vesicles.
AU - Ramachandran,Vysakh,
AU - Potoyan,Davit A,
Y1 - 2026/06/01/
PY - 2026/03/06/received
PY - 2026/05/14/revised
PY - 2026/05/15/accepted
PY - 2026/6/26/medline
PY - 2026/6/26/pubmed
PY - 2026/6/26/entrez
KW - biomolecular condensates
KW - coarse-grained simulations
KW - hollow condensates
KW - molecular grammar
KW - multiphase vesicles
KW - phase separation
KW - protein−RNA interactions
SP - 3310
EP - 3322
JF - JACS Au
JO - JACS Au
VL - 6
IS - 6
N2 - Protein-RNA phase separation gives rise to biomolecular condensates with rich internal organization, yet the molecular rules that connect sequence-encoded interactions to the emergent condensate spatial organization remain poorly understood. Here, using large-scale residue-level coarse-grained simulations, we identify a molecular grammar that governs the formation of multiphase protein-RNA condensates. We show that asymmetries in protein-protein and protein-RNA interactions, together with protein stoichiometry, chain length, and condensate density, collectively determine whether condensates adopt homogeneous, layered, biphasic, or vesicle-like morphologies. Vesicular condensates form spontaneously from well-mixed initial conditions without requiring flux-driven oversaturation or extreme charge imbalance, distinguishing this mechanism from previously proposed routes to condensate hollowing. We rationalize the full morphological progression as sequence-encoded amphiphile self-assembly: the protein-RNA complex behaves as a single-chain amphiphile whose effective packing parameter is set by Domain H/L stoichiometry, spanning micelles, cylinders, hollow vesicles, and inverse phases.
SN - 2691-3704
UR - https://www.unboundmedicine.com/prime/citation/42358691/A_Molecular_Grammar_for_Programmable_Multiphase_Protein-RNA_Vesicles.
DB - PRIME
DP - Unbound Medicine
ER -
