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

Abstract

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 C domain, a partially structured fragment located in a disordered region of fibrinogen. Polymerization of C 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. How-ever, 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. It has been postulated that oxidation of Met476 located within the C domain hinders its ability to polymerize disrupting the lateral aggregation of protofibrils and leading to the observed thinner fibers. How C 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 C-domain dimer and how this is affected by oxidation of Met476. The results suggest that multiple binding modes between two alphaC domains can occur and that oxidation decreases the likelihood of dimer formation. Furthermore, the side chain of Met476 acts as a docking spot between C domains and this function is abrogated by its conversion to methionine sulfoxide.