Actin filament remodeling by actin depolymerization factor/cofilin.

We investigate, using molecular dynamics, how the severing protein, actin depolymerization factor (ADF)/cofilin, modulates the structure, conformational dynamics, and mechanical properties of actin filaments. The actin and cofilactin filament bending stiffness and corresponding persistence lengths obtained from all-atom simulations are comparable to values obtained from analysis of thermal fluctuations in filament shape. Filament flexibility is strongly affected by the nucleotide-linked conformation of the actin subdomain 2 DNase-I binding loop and the filament radial mass density distribution. ADF/cofilin binding between subdomains 1 and 3 of a filament subunit triggers reorganization of subdomain 2 of the neighboring subunit such that the DNase-I binding loop (DB-loop) moves radially away from the filament. Repositioning of the neighboring subunit DB-loop significantly weakens subunit interactions along the long-pitch helix and lowers the filament bending rigidity. Lateral filament contacts between the hydrophobic loop and neighboring short-pitch helix monomers in native filaments are also compromised with cofilin binding. These works provide a molecular interpretation of biochemical solution studies documenting the disruption of filament subunit interactions and also reveal the molecular basis of actin filament allostery and its linkage to ADF/cofilin binding.