[Paper Review] Physics of droplet regulation in biological cells

David Zwicker, Oliver W. Paulin+1 more|ArXiv.org|Jan 23, 2025

Plant Surface Properties and Treatments4 citations

TL;DR

This is a comprehensive review of how intracellular droplets form, grow, position, and dissolve by integrating classical phase separation with cellular complexity, wetting, and active processes. It outlines theoretical frameworks and regulatory principles guiding droplet life cycles in cells and related systems.

ABSTRACT

Droplet formation has emerged as an essential concept for the spatiotemporal organisation of biomolecules in cells. However, classical descriptions of droplet dynamics based on passive liquid-liquid phase separation cannot capture the complex situation inside cells. This review discusses three distinct aspects that are crucial in cells: (i) biomolecules are diverse and individually complex, implying that cellular droplets possess complex internal behaviour, e.g., in terms of their material properties; (ii) the cellular environment contains many solid-like structures that droplets can wet; (iii) cells are alive and use fuel to drive processes out of equilibrium. We illustrate how these principles control droplet nucleation, growth, position, and count to unveil possible regulatory mechanisms in biological cells and other applications of phase separation.

Motivation & Objective

• Explain how cellular droplets form via phase separation and how nucleation, growth, and dissolution are controlled in cells.
• Describe how internal molecular complexity affects droplet material properties and dynamics.
• Elucidate how the cellular environment, including wetting by substrates and membranes, shapes droplet behavior.
• Discuss how active, out-of-equilibrium processes regulate droplet life cycles and regulation strategies.

Proposed method

• Adopt Flory–Huggins free energy framework to describe multi-component mixtures and derive chemical potentials and pressures (equations 2.1–2.5).
• Use gradient-based free-energy functionals and the Cahn–Hilliard formalism (equations 2.6–2.14) to model droplet dynamics and phase morphologies.
• Apply local interface equilibrium (Gibbs–Thomson and Laplace pressure) to relate droplet size to internal/external compositions (equations 2.30–2.32).
• Extract interfacial properties such as surface tension and width from thin-interface approximations (equations 2.25–2.27).
• Discuss both passive (diffusive/thermodynamic) and active (chemically driven) contributions to droplet regulation (section 2 vs. section 5).
• Provide scalable descriptions for droplets under heterogeneous environments, including wetting, membranes, and elastic networks (sections 4 and 3).

Experimental results

Research questions

• RQ1 How do droplets nucleate, grow, and dissolve under classical phase separation within a cellular milieu?
• RQ2 How does internal molecular complexity affect droplet material properties and dynamics?
• RQ3 In what ways do the surrounding cellular environment and wetting interactions regulate droplet size, position, and number?
• RQ4 How do active, non-equilibrium processes modify the droplet life cycle and enable regulation beyond passive phase separation?

Key findings

• Cells leverage phase separation to form biomolecular condensates that organize interiors without membranes.
• Interfacial physics, particularly Laplace pressure and Gibbs–Thomson effects, set droplet size and compositions through coexistence conditions.
• Wetting by cellular structures and membranes markedly influences droplet morphology and localization, including interactions with filaments, membranes, and elastic networks.
• Internal complexity leads to rich droplet material properties, such as viscoelasticity and potential gelation, altering dynamics
• Chemically active and externally maintained droplets can exhibit size control, drift, suppressed nucleation, and even self-division under appropriate driving and reaction schemes.
• The framework connects microscopic interactions to mesoscopic droplet behavior via thermodynamic and kinetic equations (e.g., Flory–Huggins free energy, Cahn–Hilliard dynamics) to predict regulatory mechanisms.