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Nucleotide-Dependent Actin Conformations Revealed by Multiscale Enhanced Sampling
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DOI：10.1016/j.bpj.2025.12.006.png)
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Abstract
En 中文
Actin filaments are essential components of the cytoskeleton. Their structural polarity, characterized by distinct 'plus' (barbed) and 'minus' (pointed) ends, is crucial for the directional growth and dynamic behavior of actin filaments during cellular processes such as motility, division, and intracellular transport. Asymmetric and directional filament formation is highly regulated by the bound nucleotide such that ATP-bound G-actin binds on the barbed end, ATP hydrolysis and phosphate dissociation occurs in the filament, and the resulting ADP-bound F-actin dissociates from the pointed end. In this study, we performed comprehensive conformational samplings of G-actin and F-actin, both with ATP and ADP bound, using multiscale enhanced sampling. As a simple model of F-actin, we adopted recent high-resolution crystal structures of actin complexed with actin-binding protein, fragmin domain-1. The derived conformational ensembles revealed that ATP-bound G-actin exhibits greater fluctuation and is more prone to interconvert between the G-form and F-form. This conformational flexibility will favor association with the filament over ADP-bound G-actin. In contrast, ADP-bound F-actin is more flexible and more likely to undergo deformation from the F-form, which implies dissociation of ADP-bound F-actin from the filament compared to ATP-bound F-actin. These results explain the directional nature of filament formation that ATP-bound G-actin preferentially associates with the barbed end, while ADP-bound F-actin dissociates from the pointed end. Atom contact analysis clarified that the γ-phosphate in ATP binding to actin subdomain 1 contributes to nucleotide-dependent actin flexibility.
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