AVS 47th International Symposium
    Biomaterial Interfaces Monday Sessions
       Session BI+SS-MoM

Invited Paper BI+SS-MoM3
Regulating Molecular Recognition and Self-assembly via Mechanical Forces: The Cell Adhesion Protein Fibronectin at Phospholipid Interfaces

Monday, October 2, 2000, 9:00 am, Room 202

Session: Biological Surface Science
Presenter: V. Vogel, University of Washington
Authors: A. Krammer, University of Washington
G. Baneyx, University of Washington
D. Craig, University of Washington
K. Schulten, University of Illinois at Urbana-Champaign
V. Vogel, University of Washington
Correspondent: Click to Email
While major progress has been made in the past to reveal how chemical factors regulate biorecognition, insight into pathways by which nature utilizes external forces to regulate biorecognition and signaling holds the potential for major new discoveries in biomedicine. Knowledge in this field is rudimentary since high-resolution crystallographic structures of biomolecules have mainly been obtained from equilibrated states. The role played by mechanical forces applied to the terminal ends of domains in regulating exposure of their recognition sites will be discussed here for the multidomain protein fibronectin. One of fibronectins many functions is to promote cell adhesion to surfaces. Starting from the equilibrium structure of fibronectin type III domains (FnIII), steered molecular dynamics simulations were applied to study the pathway by which their tertiary structures unravel under external forces. First we found that the accessibility of the cell recognition site on the FnIII10 domain, i.e. the RGD-loop, to integrins is reduced in an early stage of the forced unfolding pathway. Furthermore, forced unfolding studies of various fibronectin type III modules have shown that FnIII-7, FnIII-8, FnIII-9 and FnIII-10 differ considerably in their mechanical stability, and the simulations predict that FnIII-10 unfolds first. Finally, we have experimentally analyzed the pathway on which fibronectin assembles into fibrillar networks underneath phospholipid monolayers, and find again that mechanical forces are crucial to initiate its spontaneous self-assembly. Thus, spontaneous assembly of fibronectin into fibrils cannot be induced by adsorption to solid surfaces, yet it is the fibrillar state that allows cells to apply the forces needed to partially unfold fibronectin's domains.