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Open access Jul 2026

Topology-Encoded Charge Polarity Governs Multiphase Organization in Intrinsically Disordered Protein Polymer Condensates.

Synthetic biomolecular condensates offer a route to engineer compartmentalized microenvironments with tunable physicochemical properties, yet design principles for controlling their internal organization remain limited. Here, we report a minimal two-component system based on thermoresponsive intrinsically disordered protein polymers with lower critical solution temperature behavior (LCST-IDPPs), in which electrostatic topology programs liquid-liquid phase separation (LLPS). Incorporating charged residues into LCST-IDPPs suppresses phase separation under physiological conditions, whereas mixing oppositely charged, individually non-coacervating IDPPs restores LLPS as an emergent, composition-dependent process driven by multivalent intermolecular charge compensation. We compare this two-component system with a covalently linked diblock containing the same charged chains. This change in chain connectivity alters the coupling between electrostatic pairing, counterion redistribution, and LCST-driven dehydration. As a result, the balance between inter- and intrachain ionic pairing encodes the residual charge and micropolarity of the dense phase. This topology-dependent microenvironment controls condensate miscibility and drives the formation of either homogeneous or internally demixed multiphase assemblies. The condensate interior also shifts the apparent pKa of ionizable residues, indicating that phase separation modifies local acid-base equilibria and alters the effective side-chain charge. Together, these findings show how electrostatic topology influences LLPS, the dense-phase microenvironment, and mesoscale organization in IDPP condensates.

Julio Fernández-Fernández, V. Domínguez-Arca, Raúl Escribano et al. · 0 citations
Open access Sep 2026

Scaffold Affinity Tunes Biomolecular Condensate Function

Biomolecular condensates (BMCs) organize cellular biochemistry by concentrating selected molecules into dynamic membrane-free compartments. Yet the molecular parameters that determine not only whether condensates form, but also how they behave and what they do, remain poorly defined. Here we show that scaffold binding affinity (Kd) is a quantitative determinant of condensate phase behavior, internal dynamics and biochemical output. Using a modular SUMO-SIM system in which scaffold valency was held constant while binding affinity was systematically varied, we found that affinity governs the phase boundary, resistance to chemical perturbation, and molecular mobility of condensates in vitro and in human cells. In multicomponent mixtures, the highest-affinity scaffold dominated dense-phase composition and dynamics, revealing a hierarchical rule for condensate organization. Finally, affinity-dependent changes in condensate dynamics translated into tunable enzyme activity, establishing binding energetics as an engineerable parameter for programming condensate biochemistry.

Andres Reyna, Madyson O. Briggs, Alexander F. Russell et al. · 0 citations
Open access Jul 2026

Programmable Multiphasic Condensates Formed via Evaporation–Induced Phase Separation of Minimal Peptide Model

Biomolecular self‐assembly is ubiquitous in nature, encompassing both ordered and disordered structures to create sophisticated superstructures essential for complex biological functions. Protein and peptide condensates formed via liquid–liquid phase separation (LLPS) are characterize by disordered assembly, gaining significant interest due to their crucial role in physiological events and potential applications from drug delivery to biosensing. Short peptides with ordered structures have been widely explored as building blocks for nanoarchitectured materials, but they lack the disordered features that endow biological systems with flexibility and adaptability. Here we introduce a minimalistic peptide sticker‐and‐spacer model that forms biomolecular condensates with core–shell structure through phase separation and spontaneous evaporation. The design allows to derive the guidelines for programming condensate's architecture from homogeneous to multiphasic state via the selection of sticker and spacer. Furthermore, we demonstrate control over compartmentalization driven by intrinsic redox chemistry and post‐assembly modification. The condensates efficiently encapsulate and protect small‐molecule payloads and function as microreactors. The evaporation‐induced spontaneous phase separation results in solidified condensates enriched with redox‐active tyrosine, which serve as novel nano‐bioreactors, promoting selective biomineralization and formation of uniform metal–peptide nanohybrids. Therefore, our study provides a framework for the artificial design of protocells mimetic multicompartmental condensates endowed with on‐demand functionality.

Rohit Kumar, Sukantha Dey, P. Rajput et al. · 1 citation
2026

Synthetic Biomolecular Condensates: Design Principles and Applications.

This chapter describes synthetic gene circuit-based methods for applying synthetic condensates in E. coli to regulate transcription and translation and demonstrates how engineering synthetic condensates offers a new layer of cellular control for synthetic biology.

Yuefeng Ma, Leshan Yang, Yifan Dai · 0 citations
Open access Jul 2026

Programming Multidomain Peptides With Molecular Frustration Into Biomolecular Condensates

The discovery of biomolecular condensates, driven by liquid–liquid phase separation of intrinsically disordered proteins has significant impacts on both fundamental and applied science and engineering. Although most studies on biomolecular condensates focus on intrinsically disordered structures, research on the role of molecular ordering remains largely unexplored, however is beneficial for gaining new mechanistic understanding and further expand the design space of peptides for constructing functional condensates. Toward this goal, we conducted systematic studies on how molecular ordering impacts the phase behaviors of peptides using multidomain peptides (MDPs) as a model system. MDPs were designed using a molecular frustration principle in which parts of the peptides favored β-sheet assembly and parts favored disassembly. Through programming of each domain, it is evident that the phase behavior of MDPs is largely dictated by the secondary structure, and partially folded β-sheet plays a key role in driving MDPs to form condensates. We also discovered complex coacervates formed by MDPs and synthetic anionic polymers, which exhibited dramatically improved stability. Furthermore, we show enzyme-triggered condensation can be achieved using phosphorylated MDPs as the molecular precursor and alkaline phosphatase as a molecular switch, highlighting the potential of these materials for bacterial imaging and antimicrobial therapy development.

Debdatta Das, Jenny N Nguyen, Navneet Sahoo et al. · 0 citations
Open access Aug 2026

Sequence-dependent molecular asymmetry and architecture define electric potential profiles of biomolecular condensates

Biomolecular condensates, which regulate diverse cellular processes, exhibit distinct electric potential profiles. This potential gradient between the dilute and the dense phases serves as the underlying driving force mediating the unique microenvironment and electrochemical activity of condensates. However, the molecular principles encoding the electric potential profiles of condensates remain unclear. In this study, we show that molecular asymmetry is a unifying origin of electric polarization in condensates. Asymmetric protein–cation and protein–anion affinities alone generate an interfacial electric double layer and a finite potential even in condensates formed by charge-free proteins. The sign of potential gradient follows the direction of the affinity bias, and the magnitude collapses onto a single linear function of dense-phase protein volume fraction across changes in chain length, interaction strength and salt concentration. Further, chain termini preferentially occupy the condensate interface, so charges positioned asymmetrically with respect to the termini create spatial charge separation even in neutral polyampholytes. These interaction-encoded and sequence architecture-encoded asymmetries can reinforce, screen or reverse one another, allowing the magnitude and polarity of the interphase potential to be tuned through sequence design or solvent environments.

Fangke Chen, Runchen Xia, Yifan Dai et al. · 0 citations

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