Biology subjects

Grigorev, V.

Publications and source records attributed to Grigorev, V..

3 recordsLinked to original sources

bioRxiv2026

Mesoscale Heterogeneity Shapes Molecular Selectivity and Transport in Biomolecular Condensates

Growing experimental and computational evidence suggests that many condensates exhibit heterogeneous internal organization at mesoscopic length scales. How such mesoscale organization influences client selectivity and transport, however, remains poorly understood. Here, we use coarse-grained molecular dynamics simulations to compare homogeneous and heterogeneous sticker-spacer condensates with matched scaffold density, sticker fraction, and sticker-sticker interaction strength. We find that the two condensates exhibit markedly different client partitioning profiles and transport dynamics. In the heterogeneous condensate, clients sample distinct local microenvironments in a size-dependent manner, leading to pronounced differences in their transfer free energy compared with the homogeneous condensate. The heterogeneous internal organization also generates local environments with different mobilities and constraints, giving rise to transient subdiffusion and non-Gaussian displacement distributions in client motion. Our results identify mesoscale organization as an important physical factor controlling both molecular selectivity and transport in biomolecular condensates, with implications for the biochemical functions of both natural and engineered systems.

biophysics↗

bioRxiv2026

The exchange dynamics of client molecules in biomolecular condensates

Biomolecular condensates are dynamic assemblies whose functions depend on continuous exchange of molecular components with the surrounding environment. While scaffold molecules drive phase separation and condensate architecture, many functional components are clients that are recruited through interactions with the scaffold-rich environment. Despite their prevalence, how client- scaffold interactions shape client exchange dynamics remains poorly understood. Here, we develop a reaction-diffusion model for client exchange in scaffold-driven condensates, in which clients switch between a scaffold-bound state and an unbound state. Bound clients exchange through scaffold-mediated transport, whereas unbound clients diffuse through the pore space of the condensate. Using the fluorescence recovery of fully photobleached condensates as a measure of client exchange, we compare transport through these two pathways with bound-unbound conversion and identify three limiting regimes. In the slow-conversion regime, bound and unbound clients recover through distinct scaffold- and pore-mediated pathways. In the intermediate-conversion regime, recovery of bound clients becomes limited by client unbinding. In the fast-conversion regime, local equilibrium between bound and unbound clients produces an effective single-state recovery. We further propose a unifying description that connects these regimes and quantitatively captures the apparent recovery timescales extracted from numerical simulations across condensate sizes. Our results provide a framework for interpreting component-specific exchange dynamics, and highlight client size, client- scaffold binding, and condensate porosity as key regulators of client turnover in multicomponent condensates.

biophysics↗

bioRxiv2023

Conformational entropy of intrinsically disordered proteins bars intruders from biomolecular condensates

It has recently been discovered that eukaryotic cells are host to a multiplicity of biomolecular condensates. These condensates typically contain protein and/or RNA components with intrinsically disordered regions (IDRs). While IDRs have been proposed and demonstrated to play many roles in condensate biology, we suggest here an additional crucial role of IDRs, which is to exclude unwanted "intruders" from condensates. This exclusion effect arises from the large conformational entropy of IDRs, i.e., there is a high free-energy cost to occupying space that would otherwise be available to the IDRs. By combining polymer theory with sticker-spacer simulations, we show that the relevant insertion free energy increases with the concentration of IDRs in the condensate as well as with intruder size, attaining a linear scaling with surface area for large intruders. We find that at realistic IDR concentrations, particles as small as the size of an average protein (4 nm in diameter) can be more than 97% excluded from condensates. To overcome this entropic barrier, molecules must interact favorably with condensate components to be recruited as clients into condensates. Application of the developed size-exclusion theory to biological condensates suggests that condensate IDRs may play a generic exclusionary role across organisms and types of condensates.

biophysics↗