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Learning the chemical grammar of biomolecular condensates

Abstract

Biomolecular condensates compartmentalize and regulate assemblies of biomolecules engaged in vital physiological processes in cells. Specific proteins and nucleic acids engaged in shared functions occur in any one kind of condensate, suggesting that these compartments have distinct chemical specificities. Indeed, some small-molecule drugs concentrate in specific condensates due to chemical properties engendered by particular amino acids in the proteins in those condensates. Here we argue that the chemical properties that govern molecular interactions between a small molecule and biomolecules within a condensate can be ascertained for both the small molecule and the biomolecules. We propose that learning this ‘chemical grammar’, the rules describing the chemical features of small molecules that engender attraction or repulsion by the physicochemical environment of a specific condensate, should enable design of drugs with improved efficacy and reduced toxicity.

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Fig. 1: Small molecules can concentrate selectively within specific biomolecular condensates and may do so both through interactions with the chemical environment of the condensate and through interactions with target proteins or nucleic acids within the condensate.
Fig. 2: Chemical mechanisms in biomolecular condensate assembly.
Fig. 3: Biomolecular condensates composed of different protein components have different chemical environments that engender selective partitioning of biomolecules.
Fig. 4: Chemical specificity for small molecules in condensates.
Fig. 5: Cisplatin concentrates in large transcriptional condensates at driver oncogenes, where it selectively platinates oncogene regulatory DNA36.
Fig. 6: Small molecules and peptides may be designed to have chemical properties that interact with and influence condensates to improve therapeutic efficacy.

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Acknowledgements

We thank A. Dall’agnese for providing the images presented in Fig. 3a and A. Boija and K. Overholt for helpful discussions. Funding: H.R.K. is supported by a fellowship from the Damon Runyon Cancer Research Foundation (grant number 2458-22). R.A.Y. is supported by NIH grants R01 GM123511 and R01 MH104610, NCI grant CA155258, NSF grant PHY2044895, the 3D Genome Consortium of St. Jude Children’s Research Hospital, and funds from Novo Nordisk.

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H.R.K. and R.A.Y. conceived of and wrote this perspective.

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Correspondence to Henry R. Kilgore or Richard A. Young.

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R.A.Y. is a founder and shareholder of Syros Pharmaceuticals, Camp4 Therapeutics, Omega Therapeutics and Dewpoint Therapeutics. H.R.K. is a consultant of Dewpoint Therapeutics.

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Kilgore, H.R., Young, R.A. Learning the chemical grammar of biomolecular condensates. Nat Chem Biol (2022). https://doi.org/10.1038/s41589-022-01046-y

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