Molecular Mechanics

Mechanical forces are critical to numerous biological processes such as cell migration, cell adhesion, and the maintenance of cell shape and function. Proteins both exert and resist mechanical forces in the cell, altering cell signaling and biological function. In cell adhesion, for example, cell surface adhesion molecules anchor cells and transmit mechanical forces across the membranes. Adhesion dysfunction manifests in a variety of human diseases, including cancer and developmental disorders.

Our work focuses on determining how these protein machines transduce mechanical signals in the cell, and control cell function. We use precision instruments to measure the forces exerted by single adhesion proteins. With these instruments, we measure the strengths of single molecular bonds, and we precisely determine the range and magnitude of the forces. One of our main objectives is to establish how molecular structure determines the mechanical strength and dynamics of these nanoscale linkages.

To gain atomic level information on the molecular contacts stabilizing protein bonds, we complement our nanomechanics measurements with steered molecular dynamics simulations (movie). These simulations have identified critical side chain interactions that stabilize the protein bonds under force. We experimentally verified predictions based on the simulations, using a combination of site directed mutagenesis and molecular force measurements. This comprehensive approach, which combines experiment, theory, and biomolecular engineering, provides us with unique insight into the structural basis of biological nanomachines and their impact on biological function.