Studying the Effects of Methionine Oxidation on Human Fibrin with Multiscale Simulations

Abstract

Oxidation of key methionine residues on fibrin leads to reduced lateral aggregation in fibrin gels and prolonged fibrinolysis by tissue plasminogen activator. These observations may reveal the mechanism by which the detrimental changes in fibrinogen function are created by oxidative stress in both thrombotic and hemorrhagic diseases, particularly trauma induced coagulopathy. However, there is currently little understanding of which oxidized methionines are contributing to the observed gel characteristics or the molecular mechanism by which these oxidations change the fibrin structure at the molecular level. We have applied the recently developed well-tempered ensemble parallel tempering (PT-WTE) technique along with conventional molecular dynamics (MD) to investigate these changes in the structure and stability of the human fibrin D and αC regions. Both of these regions have indicated as key contributors to the mechanism of fibrin lateral aggregation. MD of the D region of human fibrin/fibrinogen shows no evidence that methionine oxidation disrupts the native state nor the stability of a bound knob ‘b’ surrogate peptide on the 350 ns time scale. PT-WTE simulations of a human homology model of the bovine N-terminal subdomain fragment from the αC domain reveal that methionine oxidation alters the conformational ensemble of the hairpin-linking region and decreases the proportion of closed structures compared to the non-oxidized αC domain. We attribute this alteration to the disruption of the hairpin-linking region's conformation, with oxidation increasing the radius of gyration for this segment.