Molecular Origins of Cofilin-Linked Changes in Actin Filament Mechanics

Abstract

The actin regulatory protein, cofilin, plays a central role in actin assembly dynamics by severing filaments and increasing the concentration of ends from which subunits add and dissociate. Cofilin binding modifies the average structure and mechanical properties of actin filaments, thereby promoting fragmentation of partially decorated filaments at boundaries of bare and cofilin-decorated segments. Despite extensive evidence for cofilin-dependent changes in filament structure and mechanics, it is unclear how the two processes are linked at the molecular level. Here, we use molecular dynamics (MD) simulations and coarse-grained (CG) analyses to evaluate the molecular origins of the changes in filament compliance due to cofilin binding. Filament subunits with bound cofilin are less “flat” and maintain a significantly more open nucleotide cleft than bare filament subunits. Decorated filament segments are less twisted, thinner (considering only actin), and less connected than their bare counterparts, which lowers the filament bending persistence length and torsional stiffness. using coarse-graining as an analytical method reveals that cofilin binding increases the average distance between the adjacent long-axis filament subunit, thereby weakening their interaction. In contrast, a fraction of lateral filament subunit contacts are closer and presumably stronger with cofilin binding. These results reveal the molecular origins of cofilin-dependent changes in actin filament mechanics that promote filament severing.