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 Remarkable structural transformations of actin bundles are driven by their initial polarity, motor activity, crosslinking, and filament treadmilling(2019) Chandrasekaran, Aravind; Papoian, Garegin; Upadhyaya, ArpitaBundled actin structures play a key role in maintaining cellular shape, in aiding force transmission to and from extracellular substrates, and in affecting cellular motility. Recent studies have also brought to light new details on stress generation, force transmission and contractility of actin bundles. In this work, we are primarily interested in the question of what determines the stability of actin bundles and what network geometries do unstable bundles eventually transition to. To address this problem, we used the MEDYAN mechano-chemical force field, modeling several micron-long actin bundles in 3D, while accounting for a comprehensive set of chemical, mechanical and transport processes. We developed a hierarchical clustering algorithm for classification of the different long time scale morphologies in our study. Our main finding is that initially unipolar bundles are significantly more stable compared with an apolar initial configuration. Filaments within the latter bundles slide easily with respect to each other due to myosin activity, producing a loose network that can be subsequently severely distorted. At high myosin concentrations, a morphological transition to aster-like geometries was observed. We also investigated how actin treadmilling rates influence bundle dynamics, and found that enhanced treadmilling leads to network fragmentation and disintegration, while this process is opposed by myosin and crosslinking activities. Interestingly, treadmilling bundles with an initial apolar geometry eventually evolve to a whole gamut of network morphologies based on relative positions of filament ends, such as sarcomere-like organization. We found that apolar bundles show a remarkable sensitivity to environmental conditions, which may be important in enabling rapid cytoskeletal structural reorganization and adaptation in response to intracellular and extracellular cues.