Revealing Topological Barriers against Knot Untying in Thermal and Mechanical Protein Unfolding by Molecular Dynamics Simulations

The knot is one of the most remarkable topological features identified in an increasing number of proteins with important functions. However, little is known about how the knot is formed during protein folding, and untied or maintained in protein unfolding. By means of all-atom molecular dynamics si...

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Autores principales:	Yan Xu, Runshan Kang, Luyao Ren, Lin Yang, Tongtao Yue
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	knotted protein folding/unfolding knot untying molecular dynamics simulation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/58fcbc6c2dd44a5ab4dd295c0c802ab9
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spelling	oai:doaj.org-article:58fcbc6c2dd44a5ab4dd295c0c802ab92021-11-25T16:53:50ZRevealing Topological Barriers against Knot Untying in Thermal and Mechanical Protein Unfolding by Molecular Dynamics Simulations10.3390/biom111116882218-273Xhttps://doaj.org/article/58fcbc6c2dd44a5ab4dd295c0c802ab92021-11-01T00:00:00Zhttps://www.mdpi.com/2218-273X/11/11/1688https://doaj.org/toc/2218-273XThe knot is one of the most remarkable topological features identified in an increasing number of proteins with important functions. However, little is known about how the knot is formed during protein folding, and untied or maintained in protein unfolding. By means of all-atom molecular dynamics simulation, here we employ methyltransferase YbeA as the knotted protein model to analyze changes of the knotted conformation coupled with protein unfolding under thermal and mechanical denaturing conditions. Our results show that the trefoil knot in YbeA is occasionally untied via knot loosening rather than sliding under enhanced thermal fluctuations. Through correlating protein unfolding with changes in the knot position and size, several aspects of barriers that jointly suppress knot untying are revealed. In particular, protein unfolding is always prior to knot untying and starts preferentially from separation of two α-helices (α1 and α5), which protect the hydrophobic core consisting of β-sheets (β1–β4) from exposure to water. These β-sheets form a loop through which α5 is threaded to form the knot. Hydrophobic and hydrogen bonding interactions inside the core stabilize the loop against loosening. In addition, residues at N-terminal of α5 define a rigid turning to impede α5 from sliding out of the loop. Site mutations are designed to specifically eliminate these barriers, and easier knot untying is achieved under the same denaturing conditions. These results provide new molecular level insights into the folding/unfolding of knotted proteins.Yan XuRunshan KangLuyao RenLin YangTongtao YueMDPI AGarticleknotted proteinfolding/unfoldingknot untyingmolecular dynamics simulationMicrobiologyQR1-502ENBiomolecules, Vol 11, Iss 1688, p 1688 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	knotted protein folding/unfolding knot untying molecular dynamics simulation Microbiology QR1-502
spellingShingle	knotted protein folding/unfolding knot untying molecular dynamics simulation Microbiology QR1-502 Yan Xu Runshan Kang Luyao Ren Lin Yang Tongtao Yue Revealing Topological Barriers against Knot Untying in Thermal and Mechanical Protein Unfolding by Molecular Dynamics Simulations
description	The knot is one of the most remarkable topological features identified in an increasing number of proteins with important functions. However, little is known about how the knot is formed during protein folding, and untied or maintained in protein unfolding. By means of all-atom molecular dynamics simulation, here we employ methyltransferase YbeA as the knotted protein model to analyze changes of the knotted conformation coupled with protein unfolding under thermal and mechanical denaturing conditions. Our results show that the trefoil knot in YbeA is occasionally untied via knot loosening rather than sliding under enhanced thermal fluctuations. Through correlating protein unfolding with changes in the knot position and size, several aspects of barriers that jointly suppress knot untying are revealed. In particular, protein unfolding is always prior to knot untying and starts preferentially from separation of two α-helices (α1 and α5), which protect the hydrophobic core consisting of β-sheets (β1–β4) from exposure to water. These β-sheets form a loop through which α5 is threaded to form the knot. Hydrophobic and hydrogen bonding interactions inside the core stabilize the loop against loosening. In addition, residues at N-terminal of α5 define a rigid turning to impede α5 from sliding out of the loop. Site mutations are designed to specifically eliminate these barriers, and easier knot untying is achieved under the same denaturing conditions. These results provide new molecular level insights into the folding/unfolding of knotted proteins.
format	article
author	Yan Xu Runshan Kang Luyao Ren Lin Yang Tongtao Yue
author_facet	Yan Xu Runshan Kang Luyao Ren Lin Yang Tongtao Yue
author_sort	Yan Xu
title	Revealing Topological Barriers against Knot Untying in Thermal and Mechanical Protein Unfolding by Molecular Dynamics Simulations
title_short	Revealing Topological Barriers against Knot Untying in Thermal and Mechanical Protein Unfolding by Molecular Dynamics Simulations
title_full	Revealing Topological Barriers against Knot Untying in Thermal and Mechanical Protein Unfolding by Molecular Dynamics Simulations
title_fullStr	Revealing Topological Barriers against Knot Untying in Thermal and Mechanical Protein Unfolding by Molecular Dynamics Simulations
title_full_unstemmed	Revealing Topological Barriers against Knot Untying in Thermal and Mechanical Protein Unfolding by Molecular Dynamics Simulations
title_sort	revealing topological barriers against knot untying in thermal and mechanical protein unfolding by molecular dynamics simulations
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/58fcbc6c2dd44a5ab4dd295c0c802ab9
work_keys_str_mv	AT yanxu revealingtopologicalbarriersagainstknotuntyinginthermalandmechanicalproteinunfoldingbymoleculardynamicssimulations AT runshankang revealingtopologicalbarriersagainstknotuntyinginthermalandmechanicalproteinunfoldingbymoleculardynamicssimulations AT luyaoren revealingtopologicalbarriersagainstknotuntyinginthermalandmechanicalproteinunfoldingbymoleculardynamicssimulations AT linyang revealingtopologicalbarriersagainstknotuntyinginthermalandmechanicalproteinunfoldingbymoleculardynamicssimulations AT tongtaoyue revealingtopologicalbarriersagainstknotuntyinginthermalandmechanicalproteinunfoldingbymoleculardynamicssimulations
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Revealing Topological Barriers against Knot Untying in Thermal and Mechanical Protein Unfolding by Molecular Dynamics Simulations

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