Structural effects of methionine oxidation on isolated subdomains of human fibrin D and αC regions.
Oxidation of key methionine residues on fibrin leads to altered fibrin polymerization producing severely altered fibrin gel structure and function. This is important because fibrinogen and its modification by oxidative stress have been implicated as key contributors to both pathological thrombotic and hemorrhagic diseases ranging from cardiovascular thrombosis to the acute coagulopathy of trauma. However, how oxidation leads to altered fibrin polymerization remains poorly understood at the molecular level. We have applied a powerful and novel well-tempered ensemble parallel tempering (PT-WTE) technique along with conventional molecular dynamics (MD) simulation to investigate the molecular-level consequences of selective methionine oxidation of fibrinogen. We offer new insights into molecular mechanisms of oxidation-induced changes in fibrin polymerization, while focusing on the D region knob 'B' and hole 'b' interaction and αC-domain interactions, both of which are hypothesized to contribute to the lateral aggregation mechanism of fibrin fibrils. Methionine oxidation did not alter the native state or the stability of a bound knob 'B' surrogate when interacting with hole 'b' in the D region. However, applying PT-WTE simulation to a human homology model of the bovine N-terminal subdomain fragment from the αC-domain revealed that methionine oxidation altered the conformation of the hairpin-linking region to favor open rather than closed hairpin structures. We attribute this alteration to the disruption of the hairpin-linking region's conformation, with oxidation increasing the radius of gyration for this segment. This result is in agreement with experimental data demonstrating decreased fibrin protofibril lateral aggregation when methionine oxidation is present in the same αC-domain fragment. Therefore, single methionine oxidation within the αC-domain is a likely molecular mechanism.
Department of Chemical Engineering, University of Washington, Seattle, Washington, United States of America.
Patrick R
PR
Burney
Puget Sound Blood Center Research Institute and Division of Emergency Medicine, University of Washington, Seattle, Washington, United States of America.
Nathan
N
White
Department of Chemical Engineering, University of Washington, Seattle, Washington, United States of America.
Jim
J
Pfaendtner
D005338:Fibrin Fibrinogen Degradation Products / Q000737:chemistry* / Q000378:metabolism; D005340:Fibrinogen / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008715:Methionine / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D058105:Polymerization; D018000:Receptors, Peptide / Q000737:chemistry* / Q000378:metabolism
D005338:Fibrin Fibrinogen Degradation Products; D018000:Receptors, Peptide; C036309:fibrin fragment D; C035637:fibrin receptor; D005340:Fibrinogen; D008715:Methionine