Bernard Lim, Eric H. Lee, Marcos Sotomayor, and Klaus Schulten.
Molecular basis of fibrin clot elasticity.
Structure, 16:449-459, 2008.
LIM2008
Blood clots must be mechanically stable to stop hemorrhage, yet elastic enough to buffer blood’s shear forces. Upsetting this balance can result in clot rupture, leading to lifethreatening thromboembolic disease including stroke, pulmonary embolism and heart attacks. With the global rise in obesity (a condition associated with cardiovascular disease) and atrial fibrillation (a disorder of heart rhythm characterized by irregularity) in world populations, cardiothromboembolic disease has reached epidemic proportions, creating an urgent need to understand and control the mechanisms that govern blood clot elasticity. Fibrin, the main component of a haemostatic plug, or blood clot, is formed from molecules of fibrinogen activated by thrombin. Although it is well known that fibrin possesses considerable elasticity, the molecular basis of this elasticity is unknown. Here we use atomic force microscopy (AFM) to probe the mechanical properties of single molecules of fibrinogen and fibrin protofibrils. The results show that the mechanical unfolding of the coiled -helices (commonly known as ‘coiled-coils’) of single fibrinogen molecules and also fibrin protofibrils is characterized by a distinctive force plateau (an intermediate transition state which has been related to elasticity) in the force-extension curve. Steered molecular dynamics (SMD) simulations of single fibrinogen molecule stretching agree closely with the AFM results and relate the plateau force to a detailed stepwise unfolding of fibrinogen’s coiled -helices and also its central domain. AFM data also show that varying pH and calcium ion concentrations alters the mechanical resilience of fibrinogen. This study provides the first direct evidence for the coiled -helices of fibrinogen as a source of fibrin elasticity and opens the way for future therapies that modulate the elasticity of blood clots, thereby potentially altering the risk for thromboembolic disease.
-helices (commonly known as ‘coiled-coils’) of single fibrinogen molecules and also fibrin protofibrils is characterized by a distinctive force plateau (an intermediate transition state which has been related to elasticity) in the force-extension curve. Steered molecular dynamics (SMD) simulations of single fibrinogen molecule stretching agree closely with the AFM results and relate the plateau force to a detailed stepwise unfolding of fibrinogen’s coiled 
