Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations

DNA G-hairpins are potential key structures participating in folding of human telomeric guanine quadruplexes (GQ). We examined their properties by standard MD simulations starting from the folded state and long T-REMD starting from the unfolded state, accumulating ∼130 μs of atomistic simulations. A...

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Main Authors:	Stadlbauer, Petr, Kührová, Petra, Banáš, Pavel, Koča, Jaroslav, Bussi, Giovanni, Trantírek, Lukáš, Otyepka, Michal, Šponer, Jiří
Format:	Online
Language:	English
Published:	Oxford University Press 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4787745/

id	pubmed-4787745
recordtype	oai_dc
spelling	pubmed-47877452016-03-14 Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations Stadlbauer, Petr Kührová, Petra Banáš, Pavel Koča, Jaroslav Bussi, Giovanni Trantírek, Lukáš Otyepka, Michal Šponer, Jiří Computational Biology DNA G-hairpins are potential key structures participating in folding of human telomeric guanine quadruplexes (GQ). We examined their properties by standard MD simulations starting from the folded state and long T-REMD starting from the unfolded state, accumulating ∼130 μs of atomistic simulations. Antiparallel G-hairpins should spontaneously form in all stages of the folding to support lateral and diagonal loops, with sub-μs scale rearrangements between them. We found no clear predisposition for direct folding into specific GQ topologies with specific syn/anti patterns. Our key prediction stemming from the T-REMD is that an ideal unfolded ensemble of the full GQ sequence populates all 4096 syn/anti combinations of its four G-stretches. The simulations can propose idealized folding pathways but we explain that such few-state pathways may be misleading. In the context of the available experimental data, the simulations strongly suggest that the GQ folding could be best understood by the kinetic partitioning mechanism with a set of deep competing minima on the folding landscape, with only a small fraction of molecules directly folding to the native fold. The landscape should further include non-specific collapse processes where the molecules move via diffusion and consecutive random rare transitions, which could, e.g. structure the propeller loops. Oxford University Press 2015-11-16 2015-10-03 /pmc/articles/PMC4787745/ /pubmed/26433223 http://dx.doi.org/10.1093/nar/gkv994 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Stadlbauer, Petr Kührová, Petra Banáš, Pavel Koča, Jaroslav Bussi, Giovanni Trantírek, Lukáš Otyepka, Michal Šponer, Jiří
spellingShingle	Stadlbauer, Petr Kührová, Petra Banáš, Pavel Koča, Jaroslav Bussi, Giovanni Trantírek, Lukáš Otyepka, Michal Šponer, Jiří Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations
author_facet	Stadlbauer, Petr Kührová, Petra Banáš, Pavel Koča, Jaroslav Bussi, Giovanni Trantírek, Lukáš Otyepka, Michal Šponer, Jiří
author_sort	Stadlbauer, Petr
title	Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations
title_short	Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations
title_full	Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations
title_fullStr	Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations
title_full_unstemmed	Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations
title_sort	hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and t-remd simulations
description	DNA G-hairpins are potential key structures participating in folding of human telomeric guanine quadruplexes (GQ). We examined their properties by standard MD simulations starting from the folded state and long T-REMD starting from the unfolded state, accumulating ∼130 μs of atomistic simulations. Antiparallel G-hairpins should spontaneously form in all stages of the folding to support lateral and diagonal loops, with sub-μs scale rearrangements between them. We found no clear predisposition for direct folding into specific GQ topologies with specific syn/anti patterns. Our key prediction stemming from the T-REMD is that an ideal unfolded ensemble of the full GQ sequence populates all 4096 syn/anti combinations of its four G-stretches. The simulations can propose idealized folding pathways but we explain that such few-state pathways may be misleading. In the context of the available experimental data, the simulations strongly suggest that the GQ folding could be best understood by the kinetic partitioning mechanism with a set of deep competing minima on the folding landscape, with only a small fraction of molecules directly folding to the native fold. The landscape should further include non-specific collapse processes where the molecules move via diffusion and consecutive random rare transitions, which could, e.g. structure the propeller loops.
publisher	Oxford University Press
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4787745/
_version_	1613550599076315136

Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations

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