Kinetics of polymer looping with macromolecular crowding: effects of volume fraction and crowder size

Abstract

The looping of polymers such as DNA is a fundamental process in the molecular biology of living cells, whose interior is characterised by a high degree of molecular crowding. We here investigate in detail the looping dynamics of flexible polymer chains in the presence of different degrees of crowding. From the analysis of the looping-unlooping rates and the looping probabilities of the chain ends we show that the presence of small crowders typically slows down the chain dynamics but larger crowders may in fact facilitate the looping. We rationalise these non-trivial and often counterintuitive effects of the crowder size on the looping kinetics in terms of an effective solution viscosity and standard excluded volume. It is shown that for small crowders the effect of an increased viscosity dominates, while for big crowders we argue that confinement effects (caging) prevail. The tradeoff between both trends can thus result in the impediment or facilitation of polymer looping, depending on the crowder size. We also examine how the crowding volume fraction, chain length, and the attraction strength of the contact groups of the polymer chain affect the looping kinetics and hairpin formation dynamics. Our results are relevant for DNA looping in the absence and presence of protein mediation, DNA hairpin formation, RNA folding, and the folding of polypeptide chains under biologically relevant high-crowding conditions.

Unusual domain movement in a multidomain protein in the presence of macromolecular crowders

“…[27][28][29][30] From the well-established Asakura-Oosawa model (AOM) 31,32 that modelled the influence of cosolutes using steric effects (and hence ascribed the observations to predominantly entropic considerations) on the incorporation of soft repulsions/interactions, the latter bringing in the enthalpic component, several modifications and advancements have been made over the years to understand the underlying interactions more comprehensively. [27][28][29][30] From the well-established Asakura-Oosawa model (AOM) 31,32 that modelled the influence of cosolutes using steric effects (and hence ascribed the observations to predominantly entropic considerations) on the incorporation of soft repulsions/interactions, the latter bringing in the enthalpic component, several modifications and advancements have been made over the years to understand the underlying interactions more comprehensively.…”

Making microenvironments: A look into incorporating macromolecular crowding into in vitro experiments, to generate biomimetic microenvironments which are capable of directing cell function for tissue engineering applications

“…Sharp 80 and other groups 81 have reported the size dependence of macromolecular crowding, concluding that generally ‘smaller is better’. In addition, other groups are developing sensors to more accurately quantify macromolecular crowding in living cells.…”

Protein abundance may regulate sensitivity to external cues in polarized cells

“…This model will account for the non-uniformly crowded cellular interior which is known to have an impact on both the diffusion coefficient and reaction rates [41][42][43][44]. We particularly wish to use this spatial model to further investigate our preliminary observations that cells that are likely to take on a soft polarization state have two-dimensional-type geometries where exchange between cytoplasmic and cortical compartments is negligible but where protein conservation plays a critical role [28,45], while hard polarization tends to occur in cells with distinct three-dimensional geometries where cytoplasmic diffusion, away from the cortex, may play a significant role such as in columnar epithelial cells or embryonic cells [6,46].…”