Observations of Twist and Disorder in F-actin from Cofilin Binding

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The regulation of actin polymerization is vital for cellular function. Cofilin is one important regulatory protein and has increasingly been credited as being a player in a cell's homeostasis. Cofilin binds and severs actin filaments, thereby leading to depolymerization and creation of new barbed ends for elongation. Mutagenesis experiments and cryo-EM work have provided critical information about the interaction of cofilin with the actin filament, however the molecular details of cofilin binding and the mechanism of twisting and severing have not been elucidated. We have performed a series of molecular docking and molecular dynamics studies using muscle actin and human cofilin I. After determining a model for bound cofilin, we performed both all-atom and coarse-grained molecular dynamics simulations on bare actin filaments, fully decorated filaments, and filaments with cofilin bound at isolated sites. We find that the binding of cofilin as domains or in isolated sites affects the average twist angles as well as the twist fluctuations. Decorated filaments not only have a greater average twist, in agreement with cryo-EM studies, but also a lower local fluctuation of twist angle. Additionally, we show how cofilin introduces local disorder in a filament. These results shine light on the cofilin's effects on F-actin twisting and bending and provide some clues about cooperative binding kinetics and filament severing.