Key result
Coarse-grained molecular dynamics simulations revealed stable configurations of the Arp2/3 complex with actin monomers and the VCA domain, and indicated a stabilizing role for the ArpC2 C-terminal tail.
Why the study?
Simulations of branch formation using all-atom molecular dynamics are challenging because of large system size and processes involving flexible regions and diffuse components.
Coarse-grained molecular dynamics simulations provide insight into the mechanisms of actin filament branch formation by the Arp2/3 complex.
Elucidates Arp2/3 branch stabilization; leaves open validation in cardiovascular cytoskeletal models.
The nucleation of actin filament branches by the Arp2/3 complex involves activation through nucleation promotion factors (NPFs), recruitment of actin monomers, and binding of the complex to the side of actin filaments. Because of the large system size and processes that involve flexible regions and diffuse components, simulations of branch formation using all-atom molecular dynamics are challenging. We applied a coarse-grained model that retains amino-acid level information and allows molecular dynamics simulations in implicit solvent, with globular domains represented as rigid bodies and flexible regions allowed to fluctuate. We used recent electron microscopy structures of the inactive Arp2/3 complex bound to NPF domains and to mother actin filament for the activated Arp2/3 complex. We studied interactions of Arp2/3 complex with the activating VCA domain of the NPF Wiskott-Aldrich syndrome protein, actin monomers, and actin filament. We found stable configurations with one or two actin monomers bound along the branch filament direction and with CA domain of VCA associated to the strong and weak binding sites of the Arp2/3 complex, supporting prior structural studies and validating our approach. We reproduced delivery of actin monomers and CA to the Arp2/3 complex under different conditions, providing insight into mechanisms proposed in previous studies. Simulations of active Arp2/3 complex bound to a mother actin filament indicate the contribution of each subunit to the binding. Addition of the C-terminal tail of Arp2/3 complex subunit ArpC2, which is missing in the cryo-EM structure, increased binding affinity, indicating a possible stabilizing role of this tail.
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Zhang et al. (2023) studied this question. Coarse-grained molecular dynamics simulations was evaluated on Interactions of Arp2/3 complex with VCA domain, actin monomers, and actin filament. Coarse-grained molecular dynamics simulations revealed stable configurations of the Arp2/3 complex with actin monomers and the VCA domain, and indicated a stabilizing role for the ArpC2 C-terminal tail.
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