Sorting of multiple molecular species on cell membranes.

Eukaryotic cells maintain their inner order by a hectic process of sorting and distillation of molecular factors taking place on their lipid membranes. A similar sorting process is implied in the assembly and budding of enveloped viruses. To understand the properties of this molecular sorting process, we have recently proposed a physical model [Zamparo et al., Phys. Rev. Lett. 126, 088101 (2021)]10.1103/PhysRevLett.126.088101, based on (1) the phase separation of a single, initially dispersed molecular species into spatially localized sorting domains on the lipid membrane and (2) domain-induced membrane bending leading to the nucleation of submicrometric lipid vesicles, naturally enriched in the molecules of the engulfed sorting domain. The analysis of the model showed the existence of an optimal region of parameter space where sorting is most efficient. Here the model is extended to account for the simultaneous distillation of a pool of distinct molecular species. We find that the mean time spent by sorted molecules on the membrane increases with the heterogeneity of the pool (i.e., the number of distinct molecular species sorted) according to a simple scaling law, and that a large number of distinct molecular species can in principle be sorted in parallel on cell membranes without significantly interfering with each other. Moreover, sorting is found to be most efficient when the distinct molecular species have comparable homotypic affinities. We also consider how valence (i.e., the average number of interacting neighbors of a molecule in a sorting domain) affects the sorting process, finding that higher-valence molecules can be sorted with greater efficiency than lower-valence molecules.

Phase separation and critical size in molecular sorting.

Molecular sorting is a fundamental process that allows eukaryotic cells to distill and concentrate specific chemical factors in appropriate cell membrane subregions, thus endowing them with different chemical identities and functional properties. A phenomenological theory of this molecular distillation process has recently been proposed [M. Zamparo, D. Valdembri, G. Serini, I. V. Kolokolov, V. V. Lebedev, L. Dall'Asta, and A. Gamba, Phys. Rev. Lett. 126, 088101 (2021)0031-900710.1103/PhysRevLett.126.088101], based on the idea that molecular sorting emerges from the combination of (a) phase separation driven formation of sorting domains and (b) domain-induced membrane bending, leading to the production of submicrometric lipid vesicles enriched in the sorted molecules. In this framework, a natural parameter controlling the efficiency of molecular distillation is the critical size of phase separated domains. In the experiments, sorting domains appear to fall into two classes: unproductive domains, characterized by short lifetimes and low probability of extraction, and productive domains, that evolve into vesicles that ultimately detach from the membrane system. It is tempting to link these two classes to the different fates predicted by classical phase separation theory for subcritical and supercritical phase separated domains. Here, we discuss the implication of this picture in the framework of the previously introduced phenomenological theory of molecular sorting. Several predictions of the theory are verified by numerical simulations of a lattice-gas model. Sorting is observed to be most efficient when the number of sorting domains is close to a minimum. To help in the analysis of experimental data, an operational definition of the critical size of sorting domains is proposed. Comparison with experimental results shows that the statistical properties of productive and unproductive domains inferred from experimental data are in agreement with those predicted from numerical simulations of the model, compatibly with the hypothesis that molecular sorting is driven by a phase separation process.

Physics of compartmentalization: How phase separation and signaling shape membrane and organelle identity.

Compartmentalization of cellular functions is at the core of the physiology of eukaryotic cells. Recent evidences indicate that a universal organizing process - phase separation - supports the partitioning of biomolecules in distinct phases from a single homogeneous mixture, a landmark event in both the biogenesis and the maintenance of membrane and non-membrane-bound organelles. In the cell, 'passive' (non energy-consuming) mechanisms are flanked by 'active' mechanisms of separation into phases of distinct density and stoichiometry, that allow for increased partitioning flexibility and programmability. A convergence of physical and biological approaches is leading to new insights into the inner functioning of this driver of intracellular order, holding promises for future advances in both biological research and biotechnological applications.