Physical theory of biological noise buffering by multicomponent phase separation

Abstract

Maintaining homeostasis is a fundamental characteristic of living systems. In cells, this is contributed to by the assembly of biochemically distinct organelles, many of which are not membrane bound but form by the physical process of liquid–liquid phase separation (LLPS). By analogy with LLPS in binary solutions, cellular LLPS was hypothesized to contribute to homeostasis by facilitating “concentration buffering,” which renders the local protein concentration within the organelle robust to global variations in the average cellular concentration (e.g., due to expression noise). Interestingly, concentration buffering was experimentally measured in vivo in a simple organelle with a single solute, while it was observed not to be obeyed in one with several solutes. Here, we formulate theoretically and solve analytically a physical model of LLPS in a ternary solution of two solutes (ϕ and ψ) that interact both homotypically (ϕ–ϕ attractions) and heterotypically (ϕ–ψ attractions). Our physical theory predicts how the coexisting concentrations in LLPS are related to expression noise and thus, generalizes the concept of concentration buffering to multicomponent systems. This allows us to reconcile the seemingly contradictory experimental observations. Furthermore, we predict that incremental changes of the homotypic and heterotypic interactions among the molecules that undergo LLPS, such as those that are caused by mutations in the genes encoding the proteins, may increase the efficiency of concentration buffering of a given system. Thus, we hypothesize that evolution may optimize concentration buffering as an efficient mechanism to maintain LLPS homeostasis and suggest experimental approaches to test this in different systems.

Rich Phase Separation Behavior of Biomolecules

“…Adding another type of solute into the system leads to drastically richer phase behaviors, as hinted by a ternary regular solution model ( Deviri and Safran, 2021 ; Dignon et al, 2020 ; Meijering, 1950 ). With additional components in the system, the phase diagram now incorporates another axis for the concentration of the second solute, and becomes three-dimensional ( Fig.…”

“…The ternary model also provides important insights regarding the noise buffering effect of phase separation. Unlike the simple buffering effect in the binary system discussed above ( Klosin et al, 2020 ), the degree of noise buffering in the ternary system varies significantly depending on the type of phase diagrams and the orientation of concentration variability imposed on the system ( Deviri and Safran, 2021 ). Indeed, recent work experimentally demonstrated that the dilute-phase concentrations of intracellular condensates are often not fixed but rather increase as the expression of protein components increases ( Riback et al, 2020 ).…”

The intertwined physics of active chemical reactions and phase separation

“…This allows for richer behavior, thus giving a better picture of real systems. In fact, even equilibrium phase separation is already complex in ternary systems since now many phases with different compositions may form [28,69,70].…”

“…However, experimentally relevant systems, and in particular biological examples, typically contain many more interacting components [75]. In fact, even ternary mixtures can display surprisingly complex phase diagram [34,69,70,76] and this trend continuous for increasing component counts [28,77]. We can now simulate systems of a few tens of components [42,43] and analyze large systems in particular cases using random matrix theory [42,[78][79][80] and scaling analysis [81].…”

Model biomolecular condensates have heterogeneous structure quantitatively dependent on the interaction profile of their constituent macromolecules

“…(1) Biomolecular condensates (BC) appear in numerous locations in cells where they carry out many biochemical functions. (2, 3) They modulate enzymatic activity,(4-7), a function that has been reproduced with rationally designed peptides;(8-10) buffer protein concentration,(11) reduce noise in gene expression,(12) and regulate cell migration. (13) Phase separation of IDPs is crucial for the healthy functioning of neuronal synapses in the presynaptic axon(14, 15) and postsynaptic dendrite.…”