Multiscale impact of nucleotides and cations on the conformational equilibrium, elasticity and rheology of actin filaments and crosslinked networks

Abstract

Cells are able to respond to mechanical forces and deformations. The actin cytoskeleton, a highly dynamic scaffolding structure, plays an important role in cell mechano-sensing. Thus, understanding rheological behaviors of the actin cytoskeleton is critical for delineating mechanical behaviors of cells. The actin cytoskeleton consists of interconnected actin filaments (F-actin) that form via self-assembly of actin monomers. It has been shown that molecular changes of the monomer subunits impact the rigidity of F-actin. However, it remains inconclusive whether or not the molecular changes can propagate to the network level and thus alter the rheological properties of actin networks. Here, we focus on how cation binding and nucleotide state tune the molecular conformation and rigidity of F-actin and a representative rheological behavior of actin networks, strain-stiffening. We employ a multiscale approach by combining established computational techniques: molecular dynamics, normal mode analysis and Brownian dynamics. Our findings indicate that different combinations of nucleotide (ATP, ADP or ADP-Pi) and cation [Formula: see text] or [Formula: see text] at one or multiple sites) binding change the molecular conformation of F-actin by varying inter- and intra-strand interactions which bridge adjacent subunits between and within F-actin helical strands. This is reflected in the rigidity of actin filaments against bending and stretching. We found that differences in extension and bending rigidity of F-actin induced by cation binding to the low-, intermediate- and high-affinity sites vary the strain-stiffening response of actin networks crosslinked by rigid crosslinkers, such as scruin, whereas they minimally impact the strain-stiffening response when compliant crosslinkers, such as filamin A or [Formula: see text]-actinin, are used.

Morphological Transformation and Force Generation of Active Cytoskeletal Networks

“…We found that during the transition from a network into a bundle, actin filaments undergo buckling and reorientation in various ways, and a large portion of tension is built during the structural reorganization rather than after bundle formation. In addition, we incorporated systematic variations of initial filament orientation that have not been included in our previous studies [13, 16, 24–27], motivated by observation that transverse arcs located at the interface between lamellipodia and lamella are formed by compaction and realignment of actin filaments with biased orientations within the lamellipodia [28]. …”

Conformational fluctuations of the AXH monomer of Ataxin-1

“…Despite the large number of experimental studies focused on the AXH domain, a similar effort has not been put on the side of molecular modelling to investigate structural and dynamics of ATH m till now. However, molecular modeling, and in particular molecular dynamics has been widely demonstrated to provide important or even exceptional insights to better understand molecular mechanisms at the basis of subcellular phenomena, such as the ones that drive protein aggregation and protein misfolding in neurodegenerative diseases …”

Nanomechanics of actin filament: A molecular dynamics simulation

“…However in modeling studies only one types of nucleotide is considered. For example, in Table 2, Li et al (2013) andBidone et al (2015) used ADP actin which is same as this study. Moreover, in Table 3, the nucleotide of Li et al (2014) is ADP and in torsional rigidity evaluation, Yasuda, Miyata, and Kinosita (1996) used ATP-AF.…”

“…Moreover, a number of previous studies focused on computer modeling of nanomechanical properties of AF. These studies can be classified base on the used method into three major groups namely, molecular dynamics (MD) simulations (Splettstoesser, Holmes, No e, & Smith, 2010Ghodsi & Kazemi, 2012), multiscale modeling (Fan, Saunders, & Voth, 2012;Deriu et al, 2011;Bidone, Kim, Deriu, Morbiducci, & Kamm, 2015;Deriu et al, 2012), and continuum mechanics modeling. All-Atoms (AA) MD simulation is used to investigate the structural modeling of F-actin (Splettstoesser et al, 2010(Splettstoesser et al, , 2011.…”