2024 AIChE Annual Meeting

(636g) Unraveling the Sequence-Dependent Conformational Transitions of Disordered Proteins during Condensation

Authors

Sundaravadivelu Devarajan, D., Texas Tech University
Kim, Y., Naval Research Laboratory
Nikoubashman, A., Princeton University
Intrinsically disordered proteins (IDPs) play a pivotal role in the formation of biomolecular condensates which are crucial to cellular function and pathology. It has been recognized that the conformation of IDPs within the condensates can critically impact the resulting properties associated with their functionality. However, a residue-level understanding of the conformational transitions of IDPs during the formation of biomolecular condensates remains elusive. Here, we utilize coarse-grained simulations of charge-patterned variants of polyampholytic model IDP1, which cover a spectrum of condensed phase behavior and single-chain conformations at infinite dilution, to reveal the sequence-dependent conformational preferences of IDPs during condensation. We find that chains partition from the dilute phase through small oligomeric clusters to a protein-enriched dense phase, accompanied by a gradual swelling of individual chains. We further demonstrate that these findings extend beyond model polyampholytes to several naturally occurring proteins involved in the formation of biologically relevant condensates2. A deeper examination of chain conformations within the condensates revealed a marked sequence-dependence at the interface3, contrasted with a minimal sequence-dependence in the dense phase. The findings in this work aid in comprehending the functional and pathological implications of conformational transitions of IDPs in the formation of biomolecular condensates.

References

(1) Sundaravadivelu Devarajan, D., Rekhi, S., Nikoubashman, A., Kim, Y. C., Howard, M. P., & Mittal, J. (2022). Effect of charge distribution on the dynamics of polyampholytic disordered proteins. Macromolecules, 55(20), 8987-8997.

(2) Wang, J., Sundaravadivelu Devarajan, D., Kim, Y. C., Nikoubashman, A., & Mittal, J. (2024). Sequence-Dependent Conformational Transitions of Disordered Proteins During Condensation. bioRxiv, 2024-01.

(3) Wang, J., Sundaravadivelu Devarajan, D., Nikoubashman, A., & Mittal, J. (2023). Conformational properties of polymers at droplet interfaces as model systems for disordered proteins. ACS Macro Letters, 12(11), 1472-1478.