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WIREs Comput Mol Sci
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Moving in the mesoscale: Understanding the mechanics of cytoskeletal molecular motors by combining mesoscale simulations with imaging

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Abstract Rapid advances in experimental biophysical techniques are generating a wealth of information about the mechanical operation of the cellular cytoskeleton and its motors. However, each of these tools typically provides only a limited piece of a highly complex puzzle. There is a need to develop new computational tools that can integrate these data together into a central model. Here we discuss the experimental advances alongside the computational tools, and propose how these could be developed to successfully combine the emerging structural and dynamic experimental data on cytoskeletal motors. We consider examples of both single motors and arrays of motors within a biological cell. This article is categorized under: Structure and Mechanism > Molecular Structures Data Science > Computer Algorithms and Programming Data Science > Visualization
Schematic representation of a super‐macromolecular array of dyneins within a primary cilium (left), and myosin 5a (Myo5a) working independently to move a cargo along the actin network (right)
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Simplified scene of actin with myosin 5a motors bound made in CellPAINT180 using the default actin available and imported PDB 1OE915
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Atomistic model of an axonemal doublet MT built from single particle cryoEM (PDB: 6U42168) visualized in UCSF ChimeraX167
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EM electron density map (gray) (EMDB: EMD‐23082) with fitted model of axonemal dynein (orange) bound to a microtubule (blue) from29 (PDB: 7KZM), visualized in UCSF Chimera164
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(Left) The particle‐based paradigm is represented by the atomistic structure of ADP‐BeF3 bound myosin 5a (PDB: 1W7J161) zoomed into the active site in visual molecular dynamics (VMD).162 (Right) The mesh paradigm is represented by a surface mesh of dimeric heavy meromyosin 5a (as seen in Figure 2d) generated using the FFEA toolset,86 visualized in Blender (https://www.blender.org/), and edited and tetrahedralised using the BlendGAMer addon163 (panel to the model's immediate right)
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An indication of scale. (a) Scale describing the temporal and spatial resolution of experimental techniques and the “biological mesoscale” (10–500 nm, 1 μs–1 s). Highest temporal resolution of super‐resolution microscopy = 50 μs (interferometric light scattering microscopy11), and force spectroscopy = 67 ms (high speed atomic force microscopy12). Highest spatial resolution of super‐resolution microscopy = 1 nm (single molecular light microscopy13), and electron microscopy (EM) = 1.2 Å (cryoEM14). Arrowless heads indicate the resolution range goes beyond the scale displayed. (b) “Bead and spring” elastic network model (ENM) of Myo5a motor domain (PDB: 1OE915) using ProDy.16,17 Arrows show anisotropic network model modes of motion. Dotted lines indicate division of motions as domains and larger beads show “hinge” regions motions predicted from Gaussian network model. Yellow = mode 1, green = mode 2, pink = mode 3. (c) CryoEM fitted model of rabbit skeletal muscle actomyosin rigor complex (PDB: 5H5318). Blue = 2 subunits of actin, orange = myosin and yellow = myosin light chain. (d) CryoEM image of dimeric Myo5a walking along actin, kindly donated by Kavitha Thirumurugan. (e) Fluctuating finite element analysis (FFEA) combined mesh (red) and rod (green, blue lines help display twist) model of dimeric Myo5a on F‐actin (blue). (f) Scanning electron micrograph (SEM) of F‐actin in a cell. (g) MEchanochemical DYnamics of Active Networks (MEDYAN) model of actin filaments bundling after 2000 s due to contractile forces from motors and cross‐linkers. Simulation box volume is 1 × 1 × 1 μm3. Blue = actin filament, orange = myosin 2 mini‐filaments, green = α‐actinin cross‐linker. Data displayed from.19 (h) Confocal image of F‐actin in a cell
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Computer and Information Science > Visualization
Computer and Information Science > Computer Algorithms and Programming
Structure and Mechanism > Molecular Structures

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