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 a...

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Autores principales:	Patrick R Burney, Nathan White, Jim Pfaendtner
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/881ef566f5b54d54bc97da58145ecd94
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spelling	oai:doaj.org-article:881ef566f5b54d54bc97da58145ecd942021-11-18T08:35:37ZStructural effects of methionine oxidation on isolated subdomains of human fibrin D and αC regions.1932-620310.1371/journal.pone.0086981https://doaj.org/article/881ef566f5b54d54bc97da58145ecd942014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24475207/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Oxidation 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.Patrick R BurneyNathan WhiteJim PfaendtnerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 1, p e86981 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Patrick R Burney Nathan White Jim Pfaendtner Structural effects of methionine oxidation on isolated subdomains of human fibrin D and αC regions.
description	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.
format	article
author	Patrick R Burney Nathan White Jim Pfaendtner
author_facet	Patrick R Burney Nathan White Jim Pfaendtner
author_sort	Patrick R Burney
title	Structural effects of methionine oxidation on isolated subdomains of human fibrin D and αC regions.
title_short	Structural effects of methionine oxidation on isolated subdomains of human fibrin D and αC regions.
title_full	Structural effects of methionine oxidation on isolated subdomains of human fibrin D and αC regions.
title_fullStr	Structural effects of methionine oxidation on isolated subdomains of human fibrin D and αC regions.
title_full_unstemmed	Structural effects of methionine oxidation on isolated subdomains of human fibrin D and αC regions.
title_sort	structural effects of methionine oxidation on isolated subdomains of human fibrin d and αc regions.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/881ef566f5b54d54bc97da58145ecd94
work_keys_str_mv	AT patrickrburney structuraleffectsofmethionineoxidationonisolatedsubdomainsofhumanfibrindandacregions AT nathanwhite structuraleffectsofmethionineoxidationonisolatedsubdomainsofhumanfibrindandacregions AT jimpfaendtner structuraleffectsofmethionineoxidationonisolatedsubdomainsofhumanfibrindandacregions
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Structural effects of methionine oxidation on isolated subdomains of human fibrin D and αC regions.

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