Motif-pattern dependence of biomolecular phase separation driven by specific interactions.

Benjamin G Weiner,Andrew G T Pyo,Yigal Meir,Ned S Wingreen,Rebecca C Wade

doi:10.1371/journal.pcbi.1009748

Benjamin G Weiner, Andrew G T Pyo + Show 3 more

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https://doi.org/10.1371/journal.pcbi.1009748

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Abstract

Eukaryotic cells partition a wide variety of important materials and processes into biomolecular condensates—phase-separated droplets that lack a membrane. In addition to nonspecific electrostatic or hydrophobic interactions, phase separation also depends on specific binding motifs that link together constituent molecules. Nevertheless, few rules have been established for how these ubiquitous specific, saturating, motif-motif interactions drive phase separation. By integrating Monte Carlo simulations of lattice-polymers with mean-field theory, we show that the sequence of heterotypic binding motifs strongly affects a polymer’s ability to phase separate, influencing both phase boundaries and condensate properties (e.g. viscosity and polymer diffusion). We find that sequences with large blocks of single motifs typically form more inter-polymer bonds, which promotes phase separation. Notably, the sequence of binding motifs influences phase separation primarily by determining the conformational entropy of self-bonding by single polymers. This contrasts with systems where the molecular architecture primarily affects the energy of the dense phase, providing a new entropy-based mechanism for the biological control of phase separation.

Highlights

Understanding how biological systems self-organize across spatial scales is one of the most pressing questions in the physics of living matter
How does a polymer’s sequence of interaction motifs affect its ability to phase separate? To address this question, we developed a lattice model where each polymer consists of a sequence of “A” and “B” motifs which form specific, saturating bonds of energy (Fig 1a and 1b)
We find that sequences with large blocks have more viscous droplets due to the strong dependence on inter-polymer bonds, in spite of their substantially lower droplet density. (See the S1 Text for off-lattice molecular-dynamics simulations that directly verify this conclusion.) By the same arguments leading to Eq 5, diffusivity scales as 1= t, so polymers with large blocks will diffuse more slowly within droplets (Fig I in S1 Text)

Summary

Introduction

Understanding how biological systems self-organize across spatial scales is one of the most pressing questions in the physics of living matter. Biomolecular condensates are thought to play a key role in physically organizing the genome and regulating gene activity [4,5,6]. Unlike the droplets of simple molecules or homopolymers, intracellular condensates are typically composed of hundreds of molecular species, each with multiple interaction motifs. How do the properties of these condensates emerge from their components, and how do cells regulate condensate formation and function? These interaction motifs can include folded domains, such as in the nephrin-Nck-N-WASP system for actin regulation [7], or individual amino acids in proteins with large intrinsically disordered regions (IDRs), such as the germ granule protein Ddx4 [8]. It remains difficult to predict the formation, properties, and composition of these diverse functional compartments

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