Proteins as mechano-chemical switches
As the equilibrium structures of proteins are typically accessible at high resolution, our understanding in drug discovery and biology is further dominated by assuming that each protein has a unique conformation which subsequently dictates its function. However, life is happening far away from equilibrium and all life forms are getting exposed to mechanical force. Much progress has been made in recent years regarding the molecular understanding of how forces can change the structure of proteins, thereby destroying molecular binding sites or alternatively open them up. Protein stretching is thus exploited by cells to sense and respond to mechanical stimuli and physical factors in their environments, which ultimately regulates gene transcription processes and subsequently cell decision making. Even though still highly disputed 20 years ago, we know today that protein stretching can switch the structure-function relationships of extracellular as well as of intracellular proteins, which defines the underpinning principles of mechanobiology.
Deciphering how proteins work as mechano-chemical switches when actuated by external or cell generated forces required to gain deep atomistic insights into the structural mechanisms how forces can influence or break secondary and tertiary structural motifs, information that can even today only be derived by steered molecular dynamic (SMD) simulations. In SMD, mechanical forces are applied to known high-resolution structures of proteins which are hydrated in boxes filled with explicit water molecules. As proteins have unique structural motives, the mechanisms by which they act as mechano-chemical switches are quite specific for each protein. Many of the structural switching mechanisms, that we have derived by SMD, have subsequently been validated experimentally.
Stretch-induced alterations of protein functions include catch bonds that hold on more tightly when exposed to tensile forces, while multivalent binding motifs can get destroyed upon stretching.
Selected reviews can be found here.