Preserving condensate structure and composition by lowering sequence complexity

Abstract

Biomolecular condensates play a vital role in organizing cellular chemistry. They selectively partition biomolecules, preventing unwanted cross talk and buffering against chemical noise. Intrinsically disordered proteins (IDPs) serve as primary components of these condensates due to their flexibility and ability to engage in multivalent interactions, leading to spontaneous aggregation. Theoretical advancements are critical at connecting IDP sequences with condensate emergent properties to establish the so-called molecular grammar. We proposed an extension to the stickers and spacers model, incorporating heterogeneous, nonspecific pairwise interactions between spacers alongside specific interactions among stickers. Our investigation revealed that although spacer interactions contribute to phase separation and co-condensation, their nonspecific nature leads to disorganized condensates. Specific sticker-sticker interactions drive the formation of condensates with well-defined networked structures and molecular composition. We discussed how evolutionary pressures might emerge to affect these interactions, leading to the prevalence of low-complexity domains in IDP sequences. These domains suppress spurious interactions and facilitate the formation of biologically meaningful condensates.

Figure 1

A schematic illustration of the stickers and random spacers model. Red spheres indicate stickers that interact specifically, and the strength for sticker-sticker interactions is a well-defined number, $-u_a$. We indicate the random spacers using shades of blue-green. These contribute nonspecific interactions, and the pairwise interactions between adjacent pairs of spacers are chosen from a normal distribution, $\mathcal{N}\left(\overline{ϵ},\Delta {ϵ}^2\right)$. To see this figure in color, go online.

Figure 2

Phase behavior of the stickers and random spacers model. (a and b) Phase diagrams for the STARS model with $\Delta ϵ=2$ (a) and the stickers and spacers model with $\Delta ϵ=0$ (b). We plot the spinodal (orange) and binodal (blue) curves that demarcate the boundaries between the stable, meta-stable, and unstable regions in the phase diagram. The critical point is highlighted in red. For the STARS model, the gel line (green) crosses the binodal twice, partitioning the stable phase into three regions. Illustrative configurations for the three regions corresponding to the solution phase, the gel phase, and the unstructured gel are shown in the bottom. (c) Dependence of the critical point on the strength of nonspecific interaction among spacers, $\Delta ϵ$. We set $u_a=5,\overline{ϵ}=0,l=10,N=100$, and $z=6$ when computing the phase diagrams. To see this figure in color, go online.

Figure 3

Impact of nonspecific interactions among spacer on the network properties of condensates. (a) The degree of conversion evaluated at ${\phi }_{\text{dense}}$ (the concentration of polymers in the dense phase) shows a moderate increase followed by a subsequent decrease as we widen the spread of the spacer-spacer interaction energy distribution by increasing $\Delta ϵ$. (b) The concentration of free chains (with all stickers free) increases with concentration in the pre-gel regime and reaches a maximum at the gel point. It monotonically decreases in the post-gel regime when $\Delta ϵ=0$, but it exhibits nonmonotonic behavior for $\Delta ϵ\ne 0$. We set $u_a=5$, $T=1$, $\overline{ϵ}=0$, $l=10$, $N=100$, and $z=6$. To see this figure in color, go online.

Figure 4

Phase diagrams showing the spinodal line (orange, solid) and binodal line (blue, dots) for a two-component system with (a) $u_{ab}=2,\Delta {ϵ}_{bb}=\Delta {ϵ}_{ab}=0$, (b) $u_{ab}=2,\Delta {ϵ}_{bb}=\Delta {ϵ}_{ab}=1.1$, (c) $u_{ab}=5,\Delta {ϵ}_{bb}=\Delta {ϵ}_{ab}=0$, and (d) $u_{ab}=5,\Delta {ϵ}_{bb}=\Delta {ϵ}_{ab}=1.1$. The tie lines (light gray, solid) connect coexisting points on the binodal. We set $N_a=N_b=10,l=2,z=6,{\overline{ϵ}}_{aa}=1,\Delta {ϵ}_{aa}=0$, and ${\overline{ϵ}}_{bb}={\overline{ϵ}}_{ab}=0$ in all systems. To see this figure in color, go online. For a Figure360 author presentation of this figure, see https://doi.org/10.1016/j.bpj.2024.05.026