title: Nucleotide regulation of the structure and dynamics of G-actin.
abstract: Actin, a highly conserved cytoskeletal protein found in all eukaryotic cells, facilitates cell motility and membrane remodeling via a directional polymerization cycle referred to as treadmilling. The nucleotide bound at the core of each actin subunit regulates this process. Although the biochemical kinetics of treadmilling has been well characterized, the atomistic details of how the nucleotide affects polymerization remain to be definitively determined. There is increasing evidence that the nucleotide regulation (and other characteristics) of actin cannot be fully described from the minimum energy structure, but rather depends on a dynamic equilibrium between conformations. In this work we explore the conformational mobility of the actin monomer (G-actin) in a coarse-grained subspace using umbrella sampling to bias all-atom molecular-dynamics simulations along the variables of interest. The results reveal that ADP-bound actin subunits are more conformationally mobile than ATP-bound subunits. We used a multiscale analysis method involving coarse-grained and atomistic representations of these simulations to characterize how the nucleotide affects the low-energy states of these systems. The interface between subdomains SD2-SD4, which is important for polymerization, is stabilized in an actin filament-like (F-actin) conformation in ATP-bound G-actin. Additionally, the nucleotide modulates the conformation of the SD1-SD3 interface, a region involved in the binding of several actin-binding proteins.
authors.affiliation: Department of Chemistry, University of Chicago, Chicago, Illinois; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois; James Franck Institute, University of Chicago, Chicago, Illinois; Computation Institute, University of Chicago, Chicago, Illinois.
authors.forename: Marissa G
authors.initials: MG
authors.lastname: Saunders
authors.affiliation: Department of Chemistry, University of Chicago, Chicago, Illinois; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois; James Franck Institute, University of Chicago, Chicago, Illinois; Computation Institute, University of Chicago, Chicago, Illinois.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Tempkin
authors.affiliation: James Franck Institute, University of Chicago, Chicago, Illinois; Department of Statistics, University of Chicago, Chicago, Illinois.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weare
authors.affiliation: Department of Chemistry, University of Chicago, Chicago, Illinois; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois; James Franck Institute, University of Chicago, Chicago, Illinois; Computation Institute, University of Chicago, Chicago, Illinois.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Dinner
authors.affiliation: Department of Chemistry, University of Chicago, Chicago, Illinois; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois; James Franck Institute, University of Chicago, Chicago, Illinois; Computation Institute, University of Chicago, Chicago, Illinois.
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
authors.affiliation: Department of Chemistry, University of Chicago, Chicago, Illinois; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois; James Franck Institute, University of Chicago, Chicago, Illinois; Computation Institute, University of Chicago, Chicago, Illinois. Electronic address: gavoth@uchicago.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Voth
mesh_terms: D000199:Actins / Q000737:chemistry* / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: C042634:ADP-G-actin; C022920:ATP-G-actin; D000199:Actins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate
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