Discrete mechanical model of lamellipodial actin network implements molecular clutch mechanism and generates arcs and microspikes.

Mechanical forces, actin filament turnover, and adhesion to the extracellular environment regulate lamellipodial protrusions. Computational and mathematical models at the continuum level have been used to investigate the molecular clutch mechanism, calculating the stress profile through the lamellip...

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Autores principales:	David M Rutkowski, Dimitrios Vavylonis
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/dd81322becda4842808da3d1062e3051
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spelling	oai:doaj.org-article:dd81322becda4842808da3d1062e30512021-12-02T19:57:29ZDiscrete mechanical model of lamellipodial actin network implements molecular clutch mechanism and generates arcs and microspikes.1553-734X1553-735810.1371/journal.pcbi.1009506https://doaj.org/article/dd81322becda4842808da3d1062e30512021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009506https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Mechanical forces, actin filament turnover, and adhesion to the extracellular environment regulate lamellipodial protrusions. Computational and mathematical models at the continuum level have been used to investigate the molecular clutch mechanism, calculating the stress profile through the lamellipodium and around focal adhesions. However, the forces and deformations of individual actin filaments have not been considered while interactions between actin networks and actin bundles is not easily accounted with such methods. We develop a filament-level model of a lamellipodial actin network undergoing retrograde flow using 3D Brownian dynamics. Retrograde flow is promoted in simulations by pushing forces from the leading edge (due to actin polymerization), pulling forces (due to molecular motors), and opposed by viscous drag in cytoplasm and focal adhesions. Simulated networks have densities similar to measurements in prior electron micrographs. Connectivity between individual actin segments is maintained by permanent and dynamic crosslinkers. Remodeling of the network occurs via the addition of single actin filaments near the leading edge and via filament bond severing. We investigated how several parameters affect the stress distribution, network deformation and retrograde flow speed. The model captures the decrease in retrograde flow upon increase of focal adhesion strength. The stress profile changes from compression to extension across the leading edge, with regions of filament bending around focal adhesions. The model reproduces the observed reduction in retrograde flow speed upon exposure to cytochalasin D, which halts actin polymerization. Changes in crosslinker concentration and dynamics, as well as in the orientation pattern of newly added filaments demonstrate the model's ability to generate bundles of filaments perpendicular (actin arcs) or parallel (microspikes) to the protruding direction.David M RutkowskiDimitrios VavylonisPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 10, p e1009506 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 David M Rutkowski Dimitrios Vavylonis Discrete mechanical model of lamellipodial actin network implements molecular clutch mechanism and generates arcs and microspikes.
description	Mechanical forces, actin filament turnover, and adhesion to the extracellular environment regulate lamellipodial protrusions. Computational and mathematical models at the continuum level have been used to investigate the molecular clutch mechanism, calculating the stress profile through the lamellipodium and around focal adhesions. However, the forces and deformations of individual actin filaments have not been considered while interactions between actin networks and actin bundles is not easily accounted with such methods. We develop a filament-level model of a lamellipodial actin network undergoing retrograde flow using 3D Brownian dynamics. Retrograde flow is promoted in simulations by pushing forces from the leading edge (due to actin polymerization), pulling forces (due to molecular motors), and opposed by viscous drag in cytoplasm and focal adhesions. Simulated networks have densities similar to measurements in prior electron micrographs. Connectivity between individual actin segments is maintained by permanent and dynamic crosslinkers. Remodeling of the network occurs via the addition of single actin filaments near the leading edge and via filament bond severing. We investigated how several parameters affect the stress distribution, network deformation and retrograde flow speed. The model captures the decrease in retrograde flow upon increase of focal adhesion strength. The stress profile changes from compression to extension across the leading edge, with regions of filament bending around focal adhesions. The model reproduces the observed reduction in retrograde flow speed upon exposure to cytochalasin D, which halts actin polymerization. Changes in crosslinker concentration and dynamics, as well as in the orientation pattern of newly added filaments demonstrate the model's ability to generate bundles of filaments perpendicular (actin arcs) or parallel (microspikes) to the protruding direction.
format	article
author	David M Rutkowski Dimitrios Vavylonis
author_facet	David M Rutkowski Dimitrios Vavylonis
author_sort	David M Rutkowski
title	Discrete mechanical model of lamellipodial actin network implements molecular clutch mechanism and generates arcs and microspikes.
title_short	Discrete mechanical model of lamellipodial actin network implements molecular clutch mechanism and generates arcs and microspikes.
title_full	Discrete mechanical model of lamellipodial actin network implements molecular clutch mechanism and generates arcs and microspikes.
title_fullStr	Discrete mechanical model of lamellipodial actin network implements molecular clutch mechanism and generates arcs and microspikes.
title_full_unstemmed	Discrete mechanical model of lamellipodial actin network implements molecular clutch mechanism and generates arcs and microspikes.
title_sort	discrete mechanical model of lamellipodial actin network implements molecular clutch mechanism and generates arcs and microspikes.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/dd81322becda4842808da3d1062e3051
work_keys_str_mv	AT davidmrutkowski discretemechanicalmodeloflamellipodialactinnetworkimplementsmolecularclutchmechanismandgeneratesarcsandmicrospikes AT dimitriosvavylonis discretemechanicalmodeloflamellipodialactinnetworkimplementsmolecularclutchmechanismandgeneratesarcsandmicrospikes
_version_	1718375872128352256

Discrete mechanical model of lamellipodial actin network implements molecular clutch mechanism and generates arcs and microspikes.

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