Oxidation-induced destabilization of the fibrinogen αC-domain dimer investigated by molecular dynamics simulations.

Upon activation, fibrinogen is converted to insoluble fibrin, which assembles into long strings called protofibrils. These aggregate laterally to form a fibrin matrix that stabilizes a blood clot. Lateral aggregation of protofibrils is mediated by the αC domain, a partially structured fragment located in a disordered region of fibrinogen. Polymerization of αC domains links multiple fibrin molecules with each other enabling the formation of thick fibrin fibers and a fibrin matrix that is stable but can also be digested by enzymes. However, oxidizing agents produced during the inflammatory response have been shown to cause thinner fibrin fibers resulting in denser clots, which are harder to proteolyze and pose the risk of deep vein thrombosis and lung embolism. Oxidation of Met located within the αC domain is thought to hinder its ability to polymerize disrupting the lateral aggregation of protofibrils and leading to the observed thinner fibers. How αC domains assemble into polymers is still unclear and yet this knowledge would shed light on the mechanism through which oxidation weakens the lateral aggregation of protofibrils. This study used temperature replica exchange molecular dynamics simulations to investigate the αC-domain dimer and how this is affected by oxidation of Met . Analysis of the trajectories revealed that multiple stable binding modes were sampled between two αC domains while oxidation decreased the likelihood of dimer formation. Furthermore, the side chain of Met was observed to act as a docking spot for the binding and this function was impaired by its conversion to methionine sulfoxide.