Chemistry & Biochemistry
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Item EMERGENT NETWORK ORGANIZATION IN LINEAR AND DENDRITIC ACTIN NETWORKS REVEALED BY MECHANOCHEMICAL SIMULATIONS(2021) Chandrasekaran, Aravind; Papoian, Garegin A; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cells employ networks of filamentous biopolymers to achieve shape changes and exert migratory forces. As the networks offer structural integrity to a cell, they are referred to as the cytoskeleton. Actin is an essential component of the cellular cytoskeleton. The organization of the actin cytoskeleton is through a combination of linear and branched filaments. Despite the knowledge of various actin-binding proteins and their interactions with individual actin filaments, the network level organization that emerges from filament level dynamics is not well understood. In this thesis, we address this issue by using advanced computer simulations that account for the complex mechanochemical dynamics of the actin networks. We begin by investigating the conditions that stabilize three critical bundle morphologies formed of linear actin filaments in the absence of external forces. We find that unipolar bundles are more stable than apolar bundles. We provide a novel mechanism for the sarcomere-like organization of bundles that have not been reported before. Then, we investigate the effect of branching nucleators, Arp2/3, on the hierarchical organization of actin in a network.By analyzing actin density fields, we find that Arp2/3 works antagonistic to myosin contractility, and excess Arp2/3 leads to spatial fragmentation of high-density actin domains. We also highlight the roles of myosin and Arp2/3 in causing the fragmentation. Finally, we understand the cooperation between the linear and dendritic filament organization strategies in the context of the growth cone. We simulate networks at various concentrations of branching molecule Arp2/3 and processive polymerase, Enabled to mimic the effect of a key axonal signaling protein, Abelson receptor non-tyrosine kinase (Abl). We find that Arp2/3 has a more substantial role in altering filament lengths and spatial actin distribution. By looking at conditions that mimic Abl signaling, we find that overexpression mimics are characterized by network fragmentation. We explore the consequence of such a fragmentation with perturbative simulations and determine that Abl overexpression causes mechanochemical fragmentation of actin networks. This finding could explain the increased developmental errors and actin fragmentation observed in vivo. Our research provides fundamental self-assembly mechanisms for linear and dendritic actin networks also highlights specific mechanochemical properties that have not been observed earlier.Item Branching activity switches actin network between connected and fragmented states in a myosin-dependent manner(2021) Chandrasekaran, Aravind; Giniger, Edward; Papoian, GareginActin networks rely on nucleation mechanisms to generate new filaments because de-novo nucleation is kinetically disfavored. Branching nucleation of actin filaments by Arp2/3, in particular, is critical for actin self-organization. In this study, we use the simulation platform for active matter, MEDYAN, to generate 2000s long stochastic trajectories of actin networks, under varying Arp2/3 concentrations, in reaction volumes of biologically meaningful size (> 20m3). We find that mechanosensitive dynamics of Arp2/3 increases the abundance of short filaments and increases network treadmilling rate. By analyzing the density-fields of F-actin, we find that at low Arp2/3 concentration, F-actin is organized into a single, connected and contractile domain, while at elevated Arp2/3 levels (10nM and above), such contractile actin domains fragment into smaller domains spanning a wide range of volumes. These fragmented domains are extremely dynamic, continuously merging and splitting, owing to the high treadmilling rate of the underlying actin network. Treating the domain dynamics as a drift-diffusion process, we find that the fragmented state is stochastically favored, and the network state slowly drifts towards the fragmented state with considerable diffusion (variability) in the number of domains. We suggest that tuning the Arp2/3 concentration enables cells to transition from a globally coherent cytoskeleton, whose response involves the entire cytoplasmic network, to a fragmented cytoskeleton where domains can respond independently to local varying signals.