Computational investigation of force generation, relaxation, and remodeling of the actin cytoskeleton

Diverse mechanics of the F-actin cytoskeleton mediate essential behaviors of cells, including cell division, migration, and shape change. Force generation by motor proteins and the resultant morphological change of cytoskeletal networks govern cellular processes such as migration and division. Cell stiffening and softening under external mechanical stimuli regulate cell shape. In this thesis, interplay between various cytoskeletal components during these processes is investigated using an agent-based computational model to elucidate mechanical factors underlying these processes. This thesis is composed of three independent studies. First, force generation in cortical actomyosin networks is studied. Using the computational model, the effects of motor activity and the density and kinetics of actin cross-linking proteins (ACPs) on the accumulation and maintenance of mechanical tension are quantitatively determined. We show that motors accumulate large stress quickly by behaving as temporary cross-linkers although this stress is relaxed over time unless there are sufficient passive ACPs to stabilize the network. Stabilization by ACPs helps motors to generate forces up to their maximum potential, significantly enhancing efficiency and stability of stress generation. Thus, it is demonstrated that the force-dependent kinetics of ACP dissociation plays a critical role in the accumulation and sustainment of stress and the structural remodeling of networks. Second, molecular origin of stress relaxation in cross-linked actin networks under shear strain is investigated. To date, stress relaxation has been mainly attributed to the transient nature of ACPs that connect F-actins. By contrast, potential effects of rich F-actin dynamics on stress relaxation have been neglected in most previous studies. In this study, it is demonstrated that F-actin severing arising from compression-induced filament buckling coordinates with ACP unbinding, leading to very distinct modes of stress relaxation. Furthermore, conditions under which the F-actin severing dominates the mechanical response are established, providing additional mechanistic insight into the viscoelasticity of the F-actin cytoskeleton. Third, formation of transverse arcs from actomyosin networks is studied. Transverse arcs form via actomyosin-driven condensation of F-actins in the lamellipodia of migrating cells and exerts significant forces on the surrounding environments. Structural reorganization of a network into a bundle facilitated by actomyosin contractility is a physiologically relevant and biophysically interesting process. Nevertheless, it remains unclear how F-actins are reoriented, buckled, and bundled as well as undergo tension buildup during the structural reorganization. In this study, how the interplay between the density of myosin motors and ACPs and the rigidity, initial orientation, and turnover of F-actins regulate the reorganization process is demonstrated