Nonspecific Yet Selective Interactions Contribute to Small Molecule Condensate Binding

Biomolecular condensates are essential in various cellular processes, and their misregulation has been demonstrated to underlie disease. Small molecules that modulate condensate stability and material properties offer promising therapeutic approaches, but mechanistic insights into their interactions...

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Bibliographic Details
Published in:Journal of chemical theory and computation 2024-11, Vol.20 (22), p.10247-10258
Main Authors: Wang, Cong, Kilgore, Henry R., Latham, Andrew P., Zhang, Bin
Format: Article
Language:English
Subjects:
Amino acids
Binding
Binding Sites
Biomolecular Systems
Chemical composition
Condensates
Hydrophobic and Hydrophilic Interactions
Hydrophobicity
Ligands
Material properties
Molecular Dynamics Simulation
Multiscale analysis
Protein Binding
Selectivity
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Thermodynamics
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Summary:Biomolecular condensates are essential in various cellular processes, and their misregulation has been demonstrated to underlie disease. Small molecules that modulate condensate stability and material properties offer promising therapeutic approaches, but mechanistic insights into their interactions with condensates remain largely lacking. We employ a multiscale approach to enable long-time, equilibrated all-atom simulations of various condensate-ligand systems. Systematic characterization of the ligand binding poses reveals that condensates can form diverse and heterogeneous chemical environments with one or multiple chains to bind small molecules. Unlike traditional protein–ligand interactions, these chemical environments are dominated by nonspecific hydrophobic interactions. Nevertheless, the chemical environments feature unique amino acid compositions and physicochemical properties that favor certain small molecules over others, resulting in varied ligand partitioning coefficients within condensates. Notably, different condensates share similar sets of chemical environments but at different populations. This population shift drives ligand selectivity toward specific condensates. Our approach can enhance the interpretation of experimental screening data and may assist in the rational design of small molecules targeting specific condensates.
ISSN:1549-9618
1549-9626
1549-9626
DOI:10.1021/acs.jctc.4c01024