Unfolding simulations of holomyoglobin from four mammals: identification of intermediates and β-sheet formation from partially unfolded states.

Myoglobin (Mb) is a centrally important, widely studied mammalian protein. While much work has investigated multi-step unfolding of apoMb using acid or denaturant, holomyoglobin unfolding is poorly understood despite its biological relevance. We present here the first systematic unfolding simulation...

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Autores principales:	Pouria Dasmeh, Kasper P Kepp
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4115b52d84cf4db3a3644eabc1f6c225
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spelling	oai:doaj.org-article:4115b52d84cf4db3a3644eabc1f6c2252021-11-18T08:40:13ZUnfolding simulations of holomyoglobin from four mammals: identification of intermediates and β-sheet formation from partially unfolded states.1932-620310.1371/journal.pone.0080308https://doaj.org/article/4115b52d84cf4db3a3644eabc1f6c2252013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24386077/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Myoglobin (Mb) is a centrally important, widely studied mammalian protein. While much work has investigated multi-step unfolding of apoMb using acid or denaturant, holomyoglobin unfolding is poorly understood despite its biological relevance. We present here the first systematic unfolding simulations of holoMb and the first comparative study of unfolding of protein orthologs from different species (sperm whale, pig, horse, and harbor seal). We also provide new interpretations of experimental mean molecular ellipticities of myoglobin intermediates, notably correcting for random coil and number of helices in intermediates. The simulated holoproteins at 310 K displayed structures and dynamics in agreement with crystal structures (R g ~1.48-1.51 nm, helicity ~75%). At 400 K, heme was not lost, but some helix loss was observed in pig and horse, suggesting that these helices are less stable in terrestrial species. At 500 K, heme was lost within 1.0-3.7 ns. All four proteins displayed exponentially decaying helix structure within 20 ns. The C- and F-helices were lost quickly in all cases. Heme delayed helix loss, and sperm whale myoglobin exhibited highest retention of heme and D/E helices. Persistence of conformation (RMSD), secondary structure, and ellipticity between 2-11 ns was interpreted as intermediates of holoMb unfolding in all four species. The intermediates resemble those of apoMb notably in A and H helices, but differ substantially in the D-, E- and F-helices, which interact with heme. The identified mechanisms cast light on the role of metal/cofactor in poorly understood holoMb unfolding. We also observed β-sheet formation of several myoglobins at 500 K as seen experimentally, occurring after disruption of helices to a partially unfolded, globally disordered state; heme reduced this tendency and sperm-whale did not display any sheet propensity during the simulations.Pouria DasmehKasper P KeppPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e80308 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pouria Dasmeh Kasper P Kepp Unfolding simulations of holomyoglobin from four mammals: identification of intermediates and β-sheet formation from partially unfolded states.
description	Myoglobin (Mb) is a centrally important, widely studied mammalian protein. While much work has investigated multi-step unfolding of apoMb using acid or denaturant, holomyoglobin unfolding is poorly understood despite its biological relevance. We present here the first systematic unfolding simulations of holoMb and the first comparative study of unfolding of protein orthologs from different species (sperm whale, pig, horse, and harbor seal). We also provide new interpretations of experimental mean molecular ellipticities of myoglobin intermediates, notably correcting for random coil and number of helices in intermediates. The simulated holoproteins at 310 K displayed structures and dynamics in agreement with crystal structures (R g ~1.48-1.51 nm, helicity ~75%). At 400 K, heme was not lost, but some helix loss was observed in pig and horse, suggesting that these helices are less stable in terrestrial species. At 500 K, heme was lost within 1.0-3.7 ns. All four proteins displayed exponentially decaying helix structure within 20 ns. The C- and F-helices were lost quickly in all cases. Heme delayed helix loss, and sperm whale myoglobin exhibited highest retention of heme and D/E helices. Persistence of conformation (RMSD), secondary structure, and ellipticity between 2-11 ns was interpreted as intermediates of holoMb unfolding in all four species. The intermediates resemble those of apoMb notably in A and H helices, but differ substantially in the D-, E- and F-helices, which interact with heme. The identified mechanisms cast light on the role of metal/cofactor in poorly understood holoMb unfolding. We also observed β-sheet formation of several myoglobins at 500 K as seen experimentally, occurring after disruption of helices to a partially unfolded, globally disordered state; heme reduced this tendency and sperm-whale did not display any sheet propensity during the simulations.
format	article
author	Pouria Dasmeh Kasper P Kepp
author_facet	Pouria Dasmeh Kasper P Kepp
author_sort	Pouria Dasmeh
title	Unfolding simulations of holomyoglobin from four mammals: identification of intermediates and β-sheet formation from partially unfolded states.
title_short	Unfolding simulations of holomyoglobin from four mammals: identification of intermediates and β-sheet formation from partially unfolded states.
title_full	Unfolding simulations of holomyoglobin from four mammals: identification of intermediates and β-sheet formation from partially unfolded states.
title_fullStr	Unfolding simulations of holomyoglobin from four mammals: identification of intermediates and β-sheet formation from partially unfolded states.
title_full_unstemmed	Unfolding simulations of holomyoglobin from four mammals: identification of intermediates and β-sheet formation from partially unfolded states.
title_sort	unfolding simulations of holomyoglobin from four mammals: identification of intermediates and β-sheet formation from partially unfolded states.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/4115b52d84cf4db3a3644eabc1f6c225
work_keys_str_mv	AT pouriadasmeh unfoldingsimulationsofholomyoglobinfromfourmammalsidentificationofintermediatesandbsheetformationfrompartiallyunfoldedstates AT kasperpkepp unfoldingsimulationsofholomyoglobinfromfourmammalsidentificationofintermediatesandbsheetformationfrompartiallyunfoldedstates
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Unfolding simulations of holomyoglobin from four mammals: identification of intermediates and β-sheet formation from partially unfolded states.

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