Membraneless organelles have garnered significant attention in the last decade for their roles in various cellular signaling functions, including sequestering proteins in phase separated droplets during stress. One of their unique properties is the ability of individual component proteins dynamically to diffuse into and out of the phase-separated aggregate controlling the rate of signaling. The rates of diffusion dictate in part how much protein or nucleic acid is available for a given cellular function. Certain mutations, however, may cause less soluble pathological aggregates, a characteristic of neurodegenerative diseases. We consider the free energy surface and its entropic and enthalpic components to explore the solubility. We compute the diffusion coefficient of peptides in aggregates to elucidate the different diffusive properties of different amino acid sequences. Seven different equilibrated peptide aggregates were simulated in periodic boundary boxes with molecular dynamics. The peptide motif was GGXGG, where X was glycine, valine, asparagine, glutamine, phenylalanine, aspartate, or arginine. The diffusion coefficients calculated for peptides in aggregate show the following trend: GGGGG &gt; GGNGG &gt; GGQGG &gt; GGVGG &gt; GGFGG. The diffusion coefficient of peptides in free solution was found to be on the order of 20 times higher than that in aggregate. Our results compared with solubility studies showed that the solubility is not a predictor of the ordering of diffusion rates.

Structure and dynamics of phase-separated liquid peptide systems

ACS Spring Meeting 2021

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