
==== Front
Res Sq
ResearchSquare
Research Square
2693-5015
American Journal Experts

39184067
10.21203/rs.3.rs-4784242/v1
10.21203/rs.3.rs-4784242
preprint
1
Article
Non-specific yet selective interactions contribute to small molecule condensate partitioning behavior
Zhang Bin https://orcid.org/0000-0002-3685-7503

Wang Cong https://orcid.org/0000-0001-5998-3740

Kilgore Henry https://orcid.org/0000-0003-4851-9656

Latham Andrew https://orcid.org/0000-0002-9338-7253

13 8 2024
rs.3.rs-4784242https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
https://www.researchsquare.com/article/rs-4784242/v1
nihpp-rs4784242v1.pdf
Abstract

Biomolecular condensates are essential in various cellular processes, and their misregulation has been demonstrated to be underly 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 non-specific 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 towards 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.
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