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Biomolecular Condensates Act as Distinct Solvation Environments that Reshape Amino Acid pK Values

Rekhi, S.; Mittal, J.

2026-01-11 biophysics
10.64898/2026.01.11.698869 bioRxiv
Show abstract

Biomolecular condensates create distinct solvation environments in which the ionization equilibria of amino acid side chains may differ markedly from those in bulk aqueous solution. Here, we use all-atom continuous constant pH molecular dynamics simulations to investigate the changes to the pKa values of titratable residues between the coexisting phases of biomolecular condensates. We find that protonated states are favored in the condensate, resulting in the stabilization of charged forms of cationic residues and neutral forms of anionic residues. The effect is consistent across condensates formed by five peptide sequences suggesting that the preference for protonated states is a universal feature of the condensate microenvironment. This highlights that differences in the solvation environments between the coexisting phases play a central role in charge regulation in phase-separating proteins.

Published in Journal of the American Chemical Society (predicted rank #5) · training set

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