Nanoscale Mechanical Recognition Switches: Inspirations from Nature

Viola Vogel

Department of Bioengineering, Box 352125, University of Washington, Seattle, WA 98195, USA


Since major progress has been made in learning how to assembly molecular building blocks into materials and thin films with defined structural architecture, some of the future challenges in Nanotechnology are to learn how to build switches on a nanoscale. It is thereby insufficient to extend macroscopic design principles to the nanoscale, most of which fail on a submicron scale. Novel design principles have to be developed, or they may be delineated through the study of biological nanoscale systems.

The focus here will be on mechanical nanoscale switches for which molecular recognition events are regulated by external forces. Steered molecular dynamics (SMD) simulations are applied to the study of the forced unfolding pathway of proteins in order to develop detailed insight how the tertiary structure of proteins is altered if tensile forces are applied. The model protein is the multidomain protein fibronectin (FN) which mediates cell attachment to surfaces by exposure of a tripeptide (RGD) sequence to cell membrane integrins.

SMD simulations now show how the exposure of this recognition site is reduced if the RGD-containing module of FN is ruptured under external forces leading to an unraveling of its tertiary structure. The relative stability of this and other modules against external forces has been determined, as well as details of the forced unfolding pathway. SMD simulations thus shed first light into potential mechanisms by which tensile forces may be utilized by Nature to regulate the accessibility of recognition sites. Once switches are built, they need to be interfaced with supporting infrastructure. If cells indeed regulate their adhesion to RGD-containing matrices by applying forces above certain threshold values, thereby inducing a partial unfolding of those RGD-modules, the modules have to be integrated into microscopic structures that allow cells to exert tensile forces. Cells are able to assemble FN into extended fibrillar structures within their extracellular matrices, however, the sequential pathway is not well known. Using an ex-vivo model system, we identified the essential steps that are required to induce FN-FN assembly into microscopic fibrils.