Oxidation-induced destabilization of the fibrinogen ?C-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. 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 Met476 located within the ?C domain is thought to hinder 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 . Analysis of the trajectories revealed that multiple stable binding modes were sampled between two ?C domains while oxidation decreased the likelihood of dimer formation. Furthermore, the side chain of Met476 was observed to act as a docking spot for the binding and this function was impaired by its conversion to methionine sulfoxide.

SUBMITTER: Pederson EN 

PROVIDER: S-EPMC6718331 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature