Effects of inflammatory conditions on the structure of fibrin clots: modeling a flexible protein dimer with molecular dynamics simulations

Abstract

Upon vascular injury, fibrin is converted from fibrinogen and polymerizes to form long protofibrils. Protofibrils laterally aggregate via the αC domain to form fibrin fibers, which bind to platelets and form a clot. Inflammation recruits pro-inflammatory neutrophils to the site of injury, which produce HOCl via myeloperoxidase. Inflammation is associated with abnormal clot morphologies, which can lead to thrombosis and bleeding. Fibrin Met^{476}, located in the αC domain, oxidizes upon exposure to myeloperoxidase-derived HOCl, which subsequently disrupts lateral aggregation and produces abnormal clots. The mechanism by which oxidation affects αC domain structure, dynamics and self-association was investigated by enhanced-sampling molecular dynamics techniques and free energy calculations. Replica exchange molecular dynamics simulations with an implicit solvent were used to efficiently sample αC-domain dimer conformations. Low-energy conformers were identified from the free energy landscape minima and were used for free energy calculations after equilibra- tion in explicit solvent. Using this method, I propose the hydrophobic core model of αC polymerization, which states that Met^{476} is a docking spot for αC polymerization.