Abstract
The structural proteins of the extracellular matrix (ECM) form fibers with finely tuned mechanical properties matched to the time scales of cell traction forces. Several proteins such as fibronectin (Fn) and fibrin undergo molecular conformational changes that extend the proteins and are believed to be a major contributor to the extensibility of bulk fibers. The dynamics of these conformational changes have been thoroughly explored since the advent of single molecule force spectroscopy and molecular dynamics simulations but remarkably, these data have not been rigorously applied to the understanding of the time dependent mechanics of bulk ECM fibers. Using measurements of protein density within fibers, we have examined the influence of dynamic molecular conformational changes and the intermolecular arrangement of Fn within fibers on the bulk mechanical properties of Fn fibers. Fibers were simulated as molecular strands with architectures that promote either equal or disparate molecular loading under conditions of constant extension rate. Measurements of protein concentration within micron scale fibers using deep ultraviolet transmission microscopy allowed the simulations to be scaled appropriately for comparison to in vitro measurements of fiber mechanics as well as providing estimates of fiber porosity and water content, suggesting Fn fibers are approximately 75% solute. Comparing the properties predicted by single molecule measurements to in vitro measurements of Fn fibers showed that domain unfolding is sufficient to predict the high extensibility and nonlinear stiffness of Fn fibers with surprising accuracy, with disparately loaded fibers providing the best fit to experiment. This work shows the promise of this microstructural modeling approach for understanding Fn fiber properties, which is generally applicable to other ECM fibers, and could be further expanded to tissue scale by incorporating these simulated fibers into three dimensional network models.
Highlights
Natural fibrillar materials possess remarkable mechanical properties that are tightly tuned to their functions, and great strides have been made toward achieving a quantitative understanding of the mechanics of these biological filaments
Our goal in this study was to use a microstructural model to determine how dynamic molecular conformational changes and the intermolecular arrangement of molecules within a fibrous material affect the bulk mechanical properties of fibronectin (Fn) fibers found in the extracellular matrix (ECM) of living cells
UV absorption microscopy To provide a scale for the model, enabling comparison of in silico and in vitro data, we first sought to determine the concentration of Fn within single fibers
Summary
Natural fibrillar materials possess remarkable mechanical properties that are tightly tuned to their functions, and great strides have been made toward achieving a quantitative understanding of the mechanics of these biological filaments. Detailed studies have shown how mechanical forces affect single molecules [1,2], single fibers [3,4], and fiber networks [5,6] in a wide range of biological materials [7,8,9,10,11], but it is difficult in many systems to link molecular properties to fiber behavior. One solution is to address these challenges with microstructural models that link molecular and fiber length scales through comparison to experimental data. Our goal in this study was to use a microstructural model to determine how dynamic molecular conformational changes and the intermolecular arrangement of molecules within a fibrous material affect the bulk mechanical properties of fibronectin (Fn) fibers found in the extracellular matrix (ECM) of living cells
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