Mechanochemical simulations of in vivo actin architectures

Abstract

Actin cytoskeleton arranges into distinct architectures to enable cell functions under different mechanochemical environments. Although recent works have revealed the key components and processes involved in actin network dynamics, how actin cytoskeleton responds to mechanical and chemical cues to assemble higher-order in vivo structures is still poorly understood. In this thesis, we use an advanced computer simulation platform to explore the mechanochemical dynamics and the physical principles underlying the formation of three ubiquitous actin scaffolds in vivo: actin bundles, dendritic lamellipodia, as well as actin rings and shell-like cortices. We first investigate the adaptive remodeling of actomyosin networks induced by a tensile external force. The application of tensile force rapidly alters filaments' orientation, followed by slower myosin motor driven contractility that gradually consolidates the structure into a thick actin bundle. These distinct actin remodeling mechanisms at short versus long timescale provide new insights to the formation of stress-fiber like actin architectures. Then, we investigate the dynamics underlying branched actin filament assembly in networks similar to lamellipodia. By varying actin branching factors and polymerization termination proteins, we reveal how individual filament assembly is related to large scale network turnover, and discuss how it affects lamellipodia driven membrane protrusion and cell migration. Lastly, we explore the question of why actomyosin networks often form ring-like or shell-like structures in cells but condense into clusters in reconstituted networks, where this structural discrepancy is regulated by a balance between myosin driven contraction and actin polymerization speed. Our works provide potential "recipes" for the assembly of cellular actin structures, in the hope of revealing the fundamental biophysical principles underlying active cytoskeleton self-organization.