Diffusion in Membraneless Organelles: A Simple Model
Caleb Huang, Dr. Gillian Lynch, Dr. Bernard Montgomery Pettitt
University of Texas Medical Branch
Introduction: Membraneless organelles have garnered significant attention in the last decade for their roles in various cellular signaling functions, including sequestering proteins during stress, facilitating patterning in the developing embryo, and assembling of snRNPs. One of their unique properties is the ability of individual component proteins to dynamically 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 more or less soluble pathological aggregates, a characteristic of neurodegenerative diseases and cancers. It is not clear whether there is a relationship between solubility or hydrophobicity and the rates of diffusion of components in an aggregate. The goal of this project is to compute the diffusion coefficient of peptides in aggregates to elucidate the diffusive properties of different amino acid sequences. Methods: Seven different equilibrated peptide aggregates were simulated in periodic boundary boxes with molecular dynamics for 38ns-46ns. The peptide motif was GGXGG, where X was glycine, valine, asparagine, glutamine, phenylalanine, aspartate, or arginine. For each of the seven peptide simulations, the average diffusion coefficient was computed for peptides while (1) in free solution, (2) in transition from aggregate to solution and vice versa, and (3) in the aggregate. Results: The diffusion coefficients calculated for peptides in aggregate show the following trend: GGGGG > GGVGG > GGQGG > GGNGG > GGFGG. The diffusion coefficient of peptides in free solution was found to be on the order of 20 times higher than that in aggregate. Conclusion: Our results compared with previous solubility studies showed that the solubility predicts the ordering of diffusion rates. While the diffusion rates do not match traditional scales of hydrophobicity, they do accurately reflect observed biological phenomena, such as polar glutamine residues being a key factor in aggregation in Huntington’s diseases. This suggests that the paradigm of hydrophobicity predicting aggregation may need to be revised. Future computational studies may delve into better understanding the chemical properties that govern diffusion rate in aggregate.