(735ad) Deciphering the Sequence-Dependent Relations between Single-Chain Protein Conformations and Their Condensed Phase Material Properties

The regular physiological functioning of many biomolecular condensates depends on their structure, dynamics, and rheology, imparted primarily by intrinsically disordered proteins (IDPs). Despite the significant effort dedicated to understanding how the sequence of IDPs drives their phase separation to form condensates, little is known about the sequence determinants of their single-chain dynamics and condensate material properties. In this work, we computationally uncover these relations for charged model and naturally occurring IDPs, prevalent in biocondensates. Specifically, we investigate how the arrangement of charged residues within these sequences influences their single-chain properties and condensate biophysical properties. At the single-chain level,^{1, 2} we find that the chain-level dynamics correlate with changes in conformation with increasing charge segregation. Importantly, the chain-level and segmental dynamics conform to simple homopolymer models only for uniformly charge-patterned sequences of the model and natural proteins. Within the condensates,³ we find diffusion, viscosity, and interfacial tension to change significantly with increasing charge segregation, but the changes are surprisingly similar between the model and natural proteins, despite their very different sequence compositions. Our simulations using implicit and explicit solvent models, reveal that molecular contacts within the condensates are highly similar to those within a single chain for all sequences. Remarkably, the condensate material properties of charged disordered proteins are strongly correlated with their dense phase contact dynamics and single-chain structural properties. Two important conclusions emerge from our work: (1) the need for caution in inferring IDP properties in dilute conditions using homopolymer scaling laws as is often done experimentally and (2) the potential utility of single-chain protein simulations in rapidly exploring varied protein sequences, thus expediting the design and prototyping of biopolymers with desired material properties in future.

References

(1) Sundaravadivelu Devarajan, D.; Rekhi, S.; Nikoubashman, A.; Kim, Y. C.; Howard, M. P.; Mittal, J. Effect of Charge Distribution on the Dynamics of Polyampholytic Disordered Proteins. Macromolecules 2022, 55 (20), 8987-8997.

(2) Wang, J.; Sundaravadivelu Devarajan, D.; Kim, Y. C.; Nikoubashman, A.; Mittal, J. Sequence-Dependent Conformational Transitions of Disordered Proteins During Condensation. bioRxiv 2024, DOI: 10.1101/2024.01.11.575294.

(3) Sundaravadivelu Devarajan, D.; Wang, J.; Szała-Mendyk, B.; Rekhi, S.; Nikoubashman, A.; Kim, Y. C.; Mittal, J. Sequence-dependent material properties of biomolecular condensates and their relation to dilute phase conformations. Nature Communications 2024, 15 (1), 1912.