Jiankuai Diao, Andrew J. Maniotis, Robert Folberg, and Emad Tajkhorshid.
Interplay of mechanical and binding properties of Fibronectin type
I.
Theoretica Chimica Acta, 125:397-405, 2010.
DIAO2010-ET
Fibronectins (FNs) are a major component of the extracellular matrix (ECM), and provide
important binding sites for a variety of ligands outside and on the surface of the cell.
Similar to other ECM proteins, FNs are consistently subject to mechanical stress in the ECM.
Therefore, it is important to study their structure and binding properties under mechanical
stress and understand how their binding and mechanical properties might affect each
other. Although certain FN modules have been extensively investigated, no simulation
studies have been reported for the FN type I (Fn1) domains, despite their prominent role in
binding of various protein modules to FN polymers in the ECM. Using equilibrium and
steered molecular dynamics simulations, we have studied mechanical properties of Fn1
modules in the presence or the absence of a specific FN-binding peptide (FnBP). We
have also investigated how the binding of the FnBP peptide to Fn1 might be affected by
tensile force. Despite the presence of disulfide bonds within individual Fn1 modules
that are presumed to prevent their extension, it is found that significant internal structural
changes within individual modules are induced by the forces applied in our simulations.
These internal structural changes result in significant variations in the accessibility of
different residues of the Fn1 modules, which affect their exposure, and, thus, the binding
properties of the Fn1 modules. Binding of the FnBP appears to reduce the flexibility of the
linker region connecting individual Fn1 modules (exhibited in the form of reduced
fluctuation and motion of the linker region), both with regard to bending and stretching
motions, and hence stabilizes the inter-domain configuration under force. Under large
tensile forces, the FnBP peptide unbinds from Fn1. The results suggest that Fn1 modules in
FN polymers do contribute to the overall extension caused by force-induced stretching of
the polymer in the ECM, and that binding properties of Fn1 modules can be affected by
mechanically induced internal protein conformational changes in spite of the presence of
disulfide bonds which were presumed to completely abolish the capacity of Fn1 modules to
undergo extension in response to external forces.
